Chemical compounds

ABSTRACT

The present invention provides a compound of a formula (I): 
                         
wherein the variables are defined herein; to a process for preparing such a compound; and to the use of such a compound in the treatment of a chemokine (such as CCR3) or H1 mediated disease state.

CROSS REFERENCE TO RELATED CASES

This application is a continuation application of, and claims priorityfrom, U.S. patent application Ser. No. 10/341,027, filed Jan. 13, 2003,now U.S. Pat. No. 6,903,115 which claims priority from U.S. patentapplication Ser. No., 09/827,488, filed Apr. 6, 2001 (now issued U.S.Pat. No. 6,525,070), which claims priority from each of UK ApplicationNo. 0008626.4, filed Apr. 8, 2000, UK Application No. 0019111.4, filed,Aug. 3, 2000, and Swedish Application No. 0003664-0, filed Oct. 11,2000. Each of the above applications is hereby incorporated by referencein its entirety.

The present invention concerns piperidine derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed inWO99/38514, WO99/04794 and WO00/35877.

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrole in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C—X—C, or α) andCys-Cys (C—C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

The C—X—C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formedfrom histidine by histidine decarboxylase. It is found in most tissuesof the body, but is present in high concentrations in the lung, skin andin the gastrointestinal tract. At the cellular level inflammatory cellssuch as mast cells and basophils store large amounts of histamine. It isrecognised that the degranulation of mast cells and basophils and thesubsequent release of histamine is a fundamental mechanism responsiblefor the clinical manifestation of an allergic process. Histamineproduces its actions by an effect on specific histamine G-proteincoupled receptors, which are of three main types, H1, H2 and H3.Histamine H1 antagonists comprise the largest class of medications usedin the treatment of patients with allergic disorders, especiallyrhinitis and urticaria. H1 antagonists are useful in controlling theallergic response by for example blocking the action of histamine onpost-capillary venule smooth muscle, resulting in decreased vascularpermeability, exudation and oedema. The antagonists also produceblockade of the actions of histamine on the H1 receptors on c-typenociceptive nerve fibres, resulting in decreased itching and sneezing.

Viral infections are known to cause lung inflammation. It has been shownexperimentally that the common cold increases mucosal output of eotaxinin the airways. Instillation of eotaxin into the nose can mimic some ofthe signs and symptoms of a common cold. (See, Greiff L et al Allergy(1999) 54(11) 1204-8 [Experimental common cold increase mucosal outputof eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch.Allergy Immunol. (2000) 122 S144 [Expression of eotaxin by normal airwayepithelial cells after virus A infection].)

The present invention provides a compound of formula (I):

wherein:

-   q, s and t are, independently, 0 or 1;-   n and r are, independently, 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2;-   X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; provided that when m and    p are both 1 then X is not CH₂;-   Y is NHR² or OH;-   T is C(O), C(S), S(O)₂ or CH₂;-   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl    or CO(C₁₋₆ alkyl);-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, CR^(3a)R^(3b)R^(3c), C₂₋₄ alkenyl {optionally    substituted by aryl or heterocyclyl}, C₃₋₇ cycloalkyl {optionally    substituted by C₁₋₄ alkyl, aryl or oxo }, C₃₋₇ cycloalkenyl    {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl,    heterocyclyl, thioaryl or thioheterocyclyl;-   R^(3a) is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₇ cycloalkyl;    R^(3b) is aryl, heterocyclyl, S(O)₂aryl or S(O)₂heterocyclyl; and    R^(3c) is C₁₋₆ alkyl, C₁₋₄ haloalkyl, hydroxy, heterocyclyl(C₁₋₄    alkyl) or aryl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl {itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by    halogen (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl,    S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally substituted    by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally    substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)},    NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy {itself optionally    substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶    or phenyl (itself optionally substituted by halogen or NO₂)}, C₁₋₆    alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O) R¹⁰,    CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³, NR⁴⁴S(O)    _(2 R) ⁴⁵, phenyl {itself optionally substituted by halogen, C₁₋₆    alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy (itself optionally    substituted by halogen, OH or pyridinyl), phenyl (itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl (itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy or C₁₋₆ haloalkoxy)}, heterocyclyl {itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy, C₁₋₆ haloalkoxy, phenyl (itself optionally substituted by    halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆    haloalkoxy) or heterocyclyl (itself optionally substituted by    halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆    haloalkoxy)}, phenoxy {itself optionally substituted by halogen,    C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,    phenyl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy)}, SCN, CN, SO₃H    (or an alkali metal salt thereof), methylenedioxy or    difluoromethylenedioxy; when aryl is phenyl adjacent substituents    may join to form, together with the phenyl ring to which they are    attached, a dihydrophenanthrene moiety;-   d is 0, 1 or 2;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹,    R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl, aryl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy);-   R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), C₃₋₆ alkenyl,    aryl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy);    or an N-oxide thereof; or a pharmaceutically acceptable salt    thereof; or a solvate thereof; provided that:    when m and p are both 1, n, q and r are all 0, T and X are both    S(O)₂, and R¹ is methoxyphenyl then R³is not propyl; when m, p, q    and r are all 1, n is 0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then    R³is not 3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or    1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q    and r are all 0, T is CO, X is NH and R¹ is    3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride,dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate,maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate. Another example of an addition salt is sulphate.

The compounds of the invention may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl groups and moieties are straight or branched chain and are, forexample, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.

Alkenyl group are, for example, vinyl or allyl.

Cycloalkyl is mono-, bi or tricyclic and is, for example, cyclopropyl,cyclopentyl, cyclohexyl, norbornyl or camphoryl. The cycloalkyl ring isoptionally fused to a benzene ring (for example forming abicyclo[4,2.0]octa-1,3,5-trienyl or indanyl ring system).

Cycloalkenyl is especially monocyclic and is, for example, cyclopentenylor cyclohexenyl.

Aryl is preferably phenyl or naphthyl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring,optionally fused to one or more other rings, comprising at least oneheteroatom selected from the group comprising nitrogen, oxygen andsulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl),pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for examplein 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl,2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl),benz[b]thienyl (also known as benzthienyl or benzthiophenyl),2,3-dihydrobenz[b]thienyl (for example in1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl,benztriazolyl, benzoxazolyl, benzthiazolyl (for example in1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, animidazopyridinyl (such as imidazo[1,2a]pyridinyl),thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known asbenzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (alsoknown as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl(for example in a coumarinyl or a chromonyl),3,4-dihydro-1H-2,1-benzothiazinyl (for example in2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (forexample 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (forexample in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example[1,6]naphthyridinyl or [1,8]naphthyridinyl or in1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl ordibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof,or an S-oxide or S-dioxide thereof.

In one aspect of the invention heterocyclyl is an aromatic ornon-aromatic 5 or 6 membered ring, optionally fused to one or more otherrings, comprising at least one heteroatom selected from the groupcomprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example,furyl, thienyl, 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,quinoxaline, dihydro-1-benzopyrylium (for example a coumarin or achromone), piperidine, morpholine, pyrrole, indole, 2,3-dihydroindole,quinoline, thiazole, pyrazole, isoxazole, imidazole, pyridine,benzofuryl, benzimidazole, pyrimidine or dibenzothiophene.

In a further aspect heterocyclyl is an aromatic or non-aromatic 5 or 6membered ring, optionally fused to one or more other rings, comprisingat least one heteroatom selected from the group comprising nitrogen,oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxidethereof. Heterocyclyl is, for example, furyl, thienyl (also known asthiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl,oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl,pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known asbenzfuryl), benz[b]thienyl (also known as benzthienyl orbenzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl,benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example2,3-dihydrobenzthiazol-2-onyl), 1,2,3-benzothiadiazolyl,1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl),2,1,3-benzothiadiazolyl, benzofurazan (also known as2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl (forexample a coumarinyl or a chromonyl), 3,4-dihydro-1H-2,1-benzothiazinyl(for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), quinolinyl,isoquinolinyl or dibenzothiophenyl (also known as dibenzothienyl); or anN-oxide thereof, or an S-oxide or S-dioxide thereof.

An N-oxide of a compound of formula (I) is, for example, a1-oxy-[1,4′]bipiperidinyl-1′-yl compound.

In another aspect the present invention provides a compound of formula(I′):

wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; mand p are, independently, 0, 1 or 2; X is CH₂, CO, O, S, S(O), S(O)₂ orNR³⁷; provided that when m and p are both 1 then X is not CH₂; Y is NHR²or OH; T is CO, CS, SO₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl orheterocyclyl; R² is hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ orphthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl oroxo}, C₃₋₇ cycloalkenyl {optionally substituted by C₁₋₆ alkyl or aryl},aryl or heterocyclyl; wherein, unless stated otherwise, the foregoingaryl and heterocyclyl moieties are optionally substituted by: halogen,OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo (such asone or two chlorine or fluorine atoms), C₁₋₆ alkyl, SO₂R³⁸ orCONR³⁹R⁴⁰), naphthyloxy (itself optionally substituted by halo or C₂₋₆alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆alkoxy (itself optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl(itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio,nitro, C₃-₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰CO₂R¹¹, CONR¹²R¹³, COR¹⁴,SO_(d)R¹⁵, SO₂NR⁴²R⁴³, NR⁴⁴SO₂R⁴⁵, phenyl (itself optionally substitutedby halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itselfoptionally substituted by halo, OH or pyridinyl)), heterocyclyl (itselfoptionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substitutedby halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) ormethylenedioxy; when aryl is phenyl adjacent substituents may join toform, together with the phenyl ring to which they are attached, adihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are,independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionallysubstituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy orC₁₋₆ haloalkoxy); RR¹⁵, R³⁸ and R⁴⁵ are, independently, C₁₋₆ alkyl oraryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceuticallyacceptable salt thereof; or a solvate thereof; provided that: when m andp are both 1, n, q and r are all 0, T and X are both SO₂, and R¹ ismethoxyphenyl then R³is not propyl; when m, p, q and r are all 1, n is0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then R³ is not3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q andr are all 0, T is CO, X is NH and R¹ is3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

In an further aspect the present invention provides a compound offormula (I), wherein: q, s and t are, independently, 0 or 1; n and rare, independently, 0, 1, 2, 3, 4 or 5; m and p are, independently, 0, 1or 2; X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; provided that when mand p are both 1 then X is not CH₂; Y is NHR² or OH; T is C(O), C(S),S(O)₂ or CH₂; R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl; R² andR⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₄alkyl); R³is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ orphthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl oroxo}, C₃₋₇ cycloalkenyl {optionally substituted by oxo, C₁₋₆ alkyl oraryl}, aryl or heterocyclyl; wherein, unless stated otherwise, theforegoing aryl and heterocyclyl moieties are optionally substituted by:halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted byhalogen, OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionallysubstituted by halo (such as one or two chlorine or fluorine atoms),C₁₋₆ alkyl, S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionallysubstituted by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itselfoptionally substituted by C-₁₋₄ alkyl or oxo) orNR⁴¹C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy(itself optionally substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆alkyl), CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by halogenor NO₂)), C₁₋₆ alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸,NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR²R⁴³,NR⁴⁴S(O)₂R⁴⁵, phenyl(itself optionally substituted by halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itself optionally substituted byhalo, OH or pyridinyl)), heterocyclyl (itself optionally substituted byhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆haloalkoxy), phenoxy (itself optionally substituted by halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H(or an alkali metal salt thereof) or methylenedioxy; when aryl is phenyladjacent substituents may join to form, together with the phenyl ring towhich they are attached, a dihydrophenanthrene moiety; d is 0, 1 or 2;R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴²,R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl or aryl (itselfoptionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are,independently, C₁₋₆ alkyl (optionally substituted by halogen, hydroxy orC₃₋₁₀ cycloalkyl) or aryl (itself optionally substituted by halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or apharmaceutically acceptable salt thereof; or a solvate thereof; providedthat: when m and p are both 1, n, q and r are all 0, T and X are bothS(O)₂, and R¹ is methoxyphenyl then R³ is not propyl; when m, p, q and rare all 1, n is 0, Y is NH₂, T is CO and R¹X is (CH₃)₂N then R³ is not3,5-dibromo-4-aminophenyl, 1-methylindol-3-yl or1-(tert-butoxycarbonyl)indol-3-yl; and when m and p are both 1, n, q andr are all 0, T is CO, X is NH and R¹ is3-(4-fluorobenzyl)benzimidazol-2-yl then R³ is not 4-fluorophenyl.

In another aspect the variables m and p are such that m+p is 0, 1 or 2(for example 1 or 2).

In a further aspect n is 0 or 1.

In a still further aspect q and r are both 0.

In another aspect n, q and r are all 0.

In another aspect m, p and t are all 1.

In a further aspect s is 0.

In another aspect s is 1. In a further aspect q is 1. In a still furtheraspect n+r is equal to more than 1 (for example n+r is equal to 2, 3, 4or 5).

In another aspect t+m+p is not equal to 3 (for example t+m+p is equal to2).

In a still further aspect X is O.

In another aspect R¹ is hydrogen, C₁₋₆ alkyl, optionally substituted (asabove) aryl or optionally substituted (as above) monocyclicheterocyclyl. In another aspect R¹ is phenyl substituted with one ormore of fluorine, chlorine, C₁₋₄ alkyl (especially methyl) or C₁₋₄alkoxy (especially methoxy).

In yet another aspect R¹ is not phenyl substituted by cycloalkyl.

In a further aspect R¹ is phenyl optionally substituted (for examplewith one, two or three) by halo (especially fluoro or chloro), C₁₋₄alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy). In astill further aspect R¹ is phenyl substituted by one, two or three of:fluoro, chloro, methyl or methoxy.

In another aspect R¹ is one of the substituted phenyl groups exemplifiedin Method F below.

In a further aspect T is C(O), S(O)₂ or CH₂. In a still further aspect Tis C(O). In another aspect T is S(O)₂ or CH₂.

In another aspect R³ is aryl or heterocyclyl either of which isoptionally substituted as described above.

In a further aspect R³ is unsubstituted phenyl, mono-substituted phenylor mono-substituted heterocyclyl, the substituents being chosen fromthose described above.

In a still further aspect R³ is oxo substituted heterocyclyl, saidheterocyclyl optionally further substituted with one or moresubstituents chosen from those described above.

In another aspect R³ is a bicyclic heterocyclyl optionally substitutedas described above. Bicyclic heterocyclyl is an aromatic or non-aromatic5 or 6 membered ring, fused to one or more other rings, comprising atleast one heteroatom selected from the group comprising nitrogen, oxygenand sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Bicyclic heterocyclyl is, for example, indolyl, 2,3-dihydroindolyl,benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known asbenzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for examplein 1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl,benztriazolyl, benzoxazolyl, benzthiazolyl (for example in1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, animidazopyridinyl (such as imidazo[1,2a]pyridinyl),thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known asbenzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (alsoknown as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl(for example in a coumarinyl or a chromonyl),3,4-dihydro-1H-2,1-benzothiazinyl (for example in2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (forexample 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (forexample in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example[1,6]naphthyridinyl or [1,8]naphthyridinyl or in1H-[1,8]naphthyridin-4-one-yl) or a benzothiazinyl (for example in4H-benzo[1,4]thiazin-3-one-yl); or an N-oxide thereof, or an S-oxide orS-dioxide thereof.

In yet another aspect R³ is: C₁₋₆ alkyl {optionally substituted byCO₂R¹⁶ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by oxo},phenyl {optionally substituted by: halogen, OH, SH, C₁₋₆ alkyl (itselfoptionally substituted by naphthyloxy (itself optionally substituted byhalo or alkenyl) or NR¹⁷C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itselfoptionally substituted by CO₂R¹⁸, NR¹⁹R²⁰ or phenyl (itself optionallysubstituted by halogen or NO₂)), C₁₋₆ alkylthio, C₁₋₄ haloalkyl, OCF₃,nitro, C₃₋₇ cycloalkyl, NR²¹R²², NR²³C(O)R²⁴, CO₂R²⁵, C(O)NR²⁶R²⁷,S(O)₂R²⁸, phenyl (itself optionally substituted by NO₂ or alkoxy (itselfoptionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO₃H (oran alkali metal salt thereof) or methylenedioxy, or adjacentsubstituents may join to form a dihydrophenanthrene moiety}, naphthyl{optionally substituted by NR²⁹R³⁰ or OH}, heterocyclyl {optionallysubstituted by halo, NO₂, oxo, C₁₋₆ alkyl (itself optionally substitutedby OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo oralkyl)), alkoxy, CF₃, thioalkyl, C(O)R³¹, CO₂R³², NR³³C(O)R³⁴, phenoxy,phenyl or nitrogen containing heterocyclyl;

-   R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁹,    R³⁰, R³¹, R³², R³³ and R³⁴ are, independently, hydrogen, C₁₋₆ alkyl    or phenyl;-   R²⁸ is C₁₋₆ alkyl; or a pharmaceutically acceptable salt thereof.

In another aspect R³ is phenyl or heterocyclyl, either of which isoptionally substituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl),C₁₋₄ alkoxy, S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2 (preferably 2); and R⁴⁶is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such ascyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

In one aspect the variable R³ can be benzo[1,2,3]thiadiazolyl,thiophenyl or phenyl; the phenyl and thiophenyl rings being optionallysubstituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itselfoptionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy,S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2 (preferably 2); and R⁴⁶ is C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such ascyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

In another aspect the variable R³ can be benzo[1 ,2,3]thiadiazolyl orphenyl (optionally substituted by: halo, hydroxy, nitro, cyano, amino,C₁₋₄ alkyl (itself optionally substituted by S(O)₂phenyl), C₁₋₄ alkoxy,S(O)_(k)R⁴⁶ (wherein k is 0, 1 or 2; and R⁴⁶ is C₁₋₄ alkyl or phenyl) orC₁₋₄ haloalkylthio.

In a still further aspect the present invention provides a compound offormula (Ia″):

wherein:

-   T is C(O), C(S), S(O)₂ or CH₂;-   n is 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2 (but are especially both 1);-   R⁵⁰ is hydrogen, cyano, S(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ haloalkyl),    halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl    (optionally substituted by one or two halogen atoms or by one    C(O)NR^(12′)R^(13′), NR^(9′)C(O)R^(10′, S(O)) ₂R^(15′), S(O)₂NR⁴²R⁴³    or NR⁴⁴S(O)₂R⁴⁵ group);-   R⁵¹ and R⁵² are, independently, hydrogen, halogen, C₁₋₄ alkyl or    C₁₋₄ alkoxy;-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl    or oxo}, aryl or heterocyclyl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or    C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or    C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself    optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself    optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,    C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,    S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆    alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,    SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;    when aryl is phenyl adjacent substituents may join to form, together    with the phenyl ring a dihydrophenanthrene moiety;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),    R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,    C₁₋₆ alkyl or phenyl;-   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;    or a pharmaceutically acceptable salt thereof.

In a further aspect R⁵⁰, R⁵¹ and R⁵² are, independently, hydrogen,halogen, (especially fluoro or chloro), C₁₋₄ alkyl (especially methyl)or C₁₋₄ alkoxy (especially methoxy).

In a still further aspect the present invention provides a compound offormula (Ia):

wherein:

-   T is C(O), C(S), S(O)₂ or CH₂;-   n is 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2 (but are especially both 1);-   R³⁵ is hydrogen, cyano, S(O)₂(C₁₋₄ alkyl), S(O)₂(C₁₋₄ haloalkyl),    halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl    (optionally substituted by one or two halogen atoms or by one    C(O)NR^(12′)R^(13′), NR^(9′)C(O)R^(10′), S(O)₂R^(15′), S(O)₂NR⁴²R⁴³    or NR^(44 S(O)) ₂R⁴⁵ group);-   R³⁶ is hydrogen, halogen or C₁₋₄ alkyl;-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl    or oxo}, aryl or heterocyclyl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or    C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or    C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself    optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself    optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,    C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,    S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆    alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,    SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;    when aryl is phenyl adjacent substituents may join to form, together    with the phenyl ring a dihydrophenanthrene moiety;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′, R)    ¹³, R^(13′, R) ¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,    C₁₋₆ alkyl or phenyl;-   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;-   or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a compound of formula(Ia′):

wherein:

-   T is CO, CS, SO₂ or CH₂;-   n is 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2 (but are especially both 1);-   R³⁵ is hydrogen, cyano, SO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ haloalkyl),    halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy or phenyl    (optionally substituted by one or two halogen atoms or by one    CONR^(12′)R^(13′), NR^(9′)COR^(10′, SO) ₂R^(15′), SO₂NR⁴²R⁴³ or    NR⁴⁴SO₂R⁴⁵ group);-   R³⁶ is hydrogen, halogen or C₁₋₄ alkyl;-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl    or oxo}, aryl or heterocyclyl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or    C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or    C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself    optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself    optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,    C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰, CO₂R¹¹, CONR¹²R¹³, COR¹⁴, SO₂R¹⁵,    phenyl (itself optionally substituted by NO₂ or C₁₋₆ alkoxy (itself    optionally substituted by OH or pyridinyl)), phenoxy, SCN, CN, SO₃H    (or an alkali metal salt thereof) or methylenedioxy; when aryl is    phenyl adjacent substituents may join to form, together with the    phenyl ring a dihydrophenanthrene moiety;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′, R)    ¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,    C₁₋₆ alkyl or phenyl;-   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or phenyl;    or a pharmaceutically acceptable salt thereof.

In a further aspect R³ is heterocyclyl (such as thienyl, isoxazolyl orindolyl, or a naphthyridinyl, an imidazopyridinyl or an isoquinolinyl)optionally substituted by oxo, halogen or C₁₋₆ alkyl.

In yet another aspect the present invention provides a compound offormula (Ia)

wherein:

-   T is C(O), C(S), S(O)₂ or CH₂;-   n is 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2;-   R³⁵ is hydrogen, halogen or phenyl (optionally substituted by one or    two halogen atoms or by one C(O)NR^(12′)R^(13′),    NR^(9′)C(O)R^(10′, S(O)) ₂R^(15′), S(O)₂NR⁴²R⁴³ or NR⁴⁴S(O)₂R⁴⁵    group);-   R³⁶ is hydrogen or halogen;-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄ alkyl    or oxo}, aryl or heterocyclyl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo or    C₁₋₆ alkyl), naphthyloxy (itself optionally substituted by halo or    C₂₋₆ alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), C₁₋₆ alkoxy (itself    optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl (itself    optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio, nitro,    C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,    S(O)₂R¹⁵, phenyl (itself optionally substituted by NO₂ or C₁₋₆    alkoxy (itself optionally substituted by OH or pyridinyl)), phenoxy,    SCN, CN, SO₃H (or an alkali metal salt thereof) or methylenedioxy;    when aryl is phenyl adjacent substituents may join to form, together    with the phenyl ring a dihydrophenanthrene moiety;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(9′), R¹⁰, R^(10′), R¹¹, R¹², R^(12′),    R¹³, R^(13′), R¹⁴, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen,    C₁₋₆ alkyl or aryl;-   R¹⁵, R^(15′) and R⁴⁵ are, independently, C₁₋₆ alkyl or aryl;    or a pharmaceutically acceptable salt thereof.

In a further aspect R³⁵ and R³⁶ are, independently, hydrogen, halogen,(especially fluoro or chloro), C₁₋₄ alkyl (especially methyl) or C₁₋₄alkoxy (especially methoxy). In another aspect R³⁵ and R³⁶ are bothchlorine or both fluorine, especially 3,4 disposed on the phenyl ring towhich they are attached.

In a further aspect the present invention provides a compound of formula(Ib):

wherein T, n and R³ are as defined above.

In a still further aspect the present invention provides a compound offormula (Ic):

wherein T, m, p and R³ are as defined above.

In another aspect the present invention provides a compound of formula(Id):

wherein R³ is as defined above.

In yet another aspect the present invention provides a compound offormula (Ie):

wherein R¹, t, s and R³ are as defined above.

In a further aspect the present invention provides a compound of formula(If):

wherein R¹, n, t, s and R³ are as defined above.

In a still further aspect the present invention provides a compound offormula (Ig):

wherein R¹, X and R³ are as defined above.

A compound of formula (I), wherein s is 0, can be prepared by coupling acompound of formula (II):

with a compound of formula (III):

wherein L is a suitable leaving group, and the variables Y and T areoptionally protected during the course of the reaction by standardprotecting groups known in the art and deprotected in a separate step orduring the reaction work-up. For example:

-   -   when T is carbonyl, L can be OH and the coupling can be carried        out in the presence of a coupling agent (such as        bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, (known        as PYBROP™), oxalyl chloride, thionyl chloride or N,N′-carbonyl        diimidazole, or another coupling agent known to a person skilled        in the art); or,    -   when T is sulphonyl, L can be chloro and the coupling can be        carrier out in the presence of a suitable base (such as        potassium carbonate) in a suitable solvent (such as acetone).

A compound of formula (I), wherein s is 1, R⁴⁷ is hydrogen and T is CO,can be prepared by reacting a compound of formula (II), wherein m and pare both 1, with an aromatic isocyanate of formula with an isocyanateO═C═N—(CH₂)_(n)—(CH₂)_(r)—R³.

A compound of formula (II) can be prepared by deprotecting a compound offormula (IV):

for example using trifluoroacetic acid in a suitable solvent (such asdichloromethane) or using a source of hydrogen chloride in a suitablesolvent (such as dioxane).

A compound of formula (IV), wherein X is O, can be prepared by reactinga compound of formula (V):

with a compound of formula (VI):

in the presence of NaBH(OAc)₃ and acetic acid.

A compound of formula (IV), wherein X is CO or CH₂, can be prepared byoxidising or reducing a compound of formula (VII):

A compound of formula (VII) can be prepared by reacting a compound offormula (VIII):

with a compound of formula (VI) in the presence of NaBH(OAc)₃ and aceticacid. A compound of formula (VIII) can be prepared by reduction of acompound of formula (IX):

A compound of formula (I) wherein X is NR³⁷ can be prepared by reactinga compound of formula (X):

with a compound of formula (XI):

in the presence of NaBH(OAc)₃ and acetic acid. A compound of formula (X)can be prepared by reacting NHR¹R³⁷ with a compound of formula (XII):

in the presence of NaBH(OAc)₃ and acetic acid and then deprotecting thepiperidine nitrogen {for example using trifluoroacetic acid in asuitable solvent (such as dichloromethane) or using a source of hydrogenchloride in a suitable solvent (such as dioxane)}.

Alternatively, a compound of formula (I), wherein s, n, q and r are all0 and T is CO, can be prepared by reacting a compound of formula (XIII):

with an acid: R³CO₂H. A compound of formula (XIII) can be prepared bydeprotecting a compound of formula (XIV):

wherein L* is BOC or a benzyl group. A compound of formula (XIV) can beprepared by performing a fluoride displacement reaction on FR¹ in thepresence of compound of formula (XV):

A compound of formula (XV) can be prepared by coupling a compound offormula (XVI) with a compound of formula (XVII):

Alternatively, a compound of formula (I) wherein s, n, q and r are all 0and T is CO, can be prepared by performing a fluoride displacementreaction on FR¹ in the presence of compound of formula (XVIII):

provided that R⁴⁷ is not hydrogen.

A compound of formula (XVIII) can be prepared by reacting a compound offormula (XIX):

with an appropriate mixed anhydride (such as an anhydride of formulaR³C(O)OC(O)(C₁₋₆ alkyl), wherein alkyl is, for example, methyl, ethyl oriso-butyl). A compound of formula (XIX) can be prepared by deprotectinga compound of formula (XV).

Alternatively, a compound of formula (I) can be prepared by reductiveammination of a compound of formula (XX):

with an amine of formula (XXI):

under suitable conditions.

Further compounds of formula (I) can be prepared by adaptation of: theroutes described above, methods described in the art or the Examplesrecited below.

Compounds of formula (V), (VI), (IX), (XI), (XII), (XVI) and (XVII) canbe prepared by using or adapting methods described in the art.

In another aspect the present invention provides processes for thepreparation of compounds of formula (I) (as defined above), (I′), (Ia″),(Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) and (Ig).

The intermediates of formula (II), (IV), (XIII), (XIV) and (XVII)defined herein are novel and these, and processes for their preparation,are provided as further features of the invention.

Examples of compounds of formula (Ib) are listed in Table I below.

TABLE 1 Compound T n R³ M + H 1 C(O) 0 C₆H₅ 433 2 C(O) 0 3,4-Cl₂—C₆H₃501 3 C(O) 0 2,4-Cl₂—C₆H₃ 501 4 C(O) 0 4-CH₃—C₆H₄ 447 5 C(O) 04-CH₃O—C₆H₄ 463 6 C(O) 0 4-CF₃—C₆H₄ 501 7 C(O) 0 4-Cl—C₆H₄ 467 8 C(O) 04-NO₂—C₆H₄ 478 9 C(O) 0 3,5-Cl₂—C₆H₃ 501 10 C(O) 0 2-F—C₆H₄ 451 11 C(O)0 4-cyclohexyl-C₆H₄ 515 12 C(O) 0 4-(n-butoxy)-C₆H₄ 505 13 C(O) 03-NMe₂-C₆H₄ 476 14 C(O) 0 4-(NHC(O)Me)-C₆H₄ 490 15 C(O) 0 4-NEt₂-C₆H₄504 16 C(O) 0 3-CO₂Me-C₆H₄ 491 17 C(O) 0 2-C(O)NH₂—C₆H₄ 18 C(O) 04-S(O)₂Me-C₆H₄ 511 19 C(O) 0 2-I—C₆H₄ 559 20 C(O) 0 3-phenoxy-C₆H₄ 52521 C(O) 0 2-Me-C₆H₄ 447 22 C(O) 0 3-Me-C₆H₄ 447 23 C(O) 0 3-I—C₆H₄ 55924 C(O) 0 3-NH₂-6-(NHC₆H₅)—C₆H₃ 539 25 C(O) 0 3,5-F₂—C₆H₃ 469 26 C(O) 03-NO₂-4-(tert-Bu)-C₆H₃ 534 27 C(O) 0 3-NO₂-5-(CO₂Me)-C₆H₃ 536 28 C(O) 02-Me-5-NO₂—C₆H₃ 492 29 C(O) 0 3,5-(tert-Bu)2-C₆H₃ 545 30 C(O) 02-NO₂-5-Me-C₆H₃ 492 31 C(O) 0 2-Br-5-MeO—C₆H₃ 541 32 C(O) 03-MeO-4-(CO₂Me)-C₆H₃ 33 C(O) 0 2-(NHC(O)Me)-5-Br—C₆H₃ 568 34 C(O) 02-NO₂-5-SCN—C₆H₃ 535 35 C(O) 0 3-MeO-4-Me-C₆H₃ 477 36 C(O) 0 4-CN—C₆H₄458 37 C(O) 0 3-CN—C₆H₄ 458 38 C(O) 0 2-phenoxy-4-Br—C₆H₃ 39 C(O) 02-NH₂-5-I—C₆H₃ 574 40 C(O) 0 4-F-C₆H₄ 451 41 S(O)₂ 0 2-CF₃O—C₆H₄ 553 42S(O)₂ 0 3-NO₂-4-Cl—C₆H₃ 548 43 S(O)₂ 0 Camphor-10-yl(alternatively named7,7- 543 dimethyl-bicyclo [2.2.1]heptan-2-on-1-yl) 44 S(O)₂ 0 n-Pr 43545 S(O)₂ 0 C₆Me₅ 539 46 S(O)₂ 0 4-(n-Pr)—C₆H₄ 511 47 S(O)₂ 0 Naphth-2-yl519 48 S(O)₂ 0 2,6-Cl₂—C₆H₃ 537 49 S(O)₂ 0 2,6-F₂—C₆H₃ 505 50 S(O)₂ 04-NO₂—C₆H₄ 514 51 S(O)₂ 0 3,4-Cl₂—C₆H₃ 537 52 S(O)₂ 0 2,5-Cl₂—C₆H₃ 53S(O)₂ 0 5-(NMe₂)-naphth-1-yl 562 54 S(O)₂ 0 2,1,3-benzthiadiazol-4-yl527 55 S(O)₂ 0 4-Et-C₆H₄ 497 56 S(O)₂ 0 2,5-Cl₂-thien-3-yl 543 57 S(O)₂0 3,4-(MeO)₂—C₆H₃ 529 58 S(O)₂ 0 3-CF₃-6-Cl—C₆H₃ 571 59 S(O)₂ 05-Cl-thien-2-yl 509 60 S(O)₂ 0 4-Cl—C₆H₄ 503 61 S(O)₂ 0 4-(iso-Pr)—C₆H₄511 62 S(O)₂ 0 2-Cl-4-CF₃—C₆H₃ 571 63 S(O)₂ 0 Benzofuraz-4-yl(other name2,1,3-benzoxadiazol-4-yl 511 64 S(O)₂ 0 3-Me-C₆H₄ 483 65 S(O)₂ 02,4-F₂—C₆H₃ 505 66 S(O)₂ 0 2-Me-5-F-C₆H₃ 501 67 S(O)₂ 0 4-CF₃O—C₆H₄ 55368 S(O)₂ 0 iso-Pr 435 70 S(O)₂ 0 4-(CO₂H)-C₆H₄ 513 71 S(O)₂ 0chromen-2-one-6-yl 537 72 S(O)₂ 0 3,5-Cl₂—C₆H₃ 537 73 S(O)₂ 02,3-Cl₂—C₆H₃ 537 74 S(O)₂ 1 4-NO₂—C₆H₄ 75 S(O)₂ 0 3-CF₃—C₆H₄ 537 76S(O)₂ 0 4-(tert-Bu)-C₆H₄ 525 77 S(O)₂ 0 3-CO₂H-4-OH—C₆H₃ 529 78 S(O)₂ 02-NO₂—C₆H₄ 514 79 S(O)₂ 0 2-F-C₆H₄ 487 80 S(O)₂ 0 3-NO₂—C₆H₄ 514 83S(O)₂ 0 Naphth-1-yl 519 84 S(O)₂ 0 2-MeO-5-Cl—C₆H₃ 533 85 S(O)₂ 03-F—C₆H₄ 487 86 S(O)₂ 0 3-Cl-4-(NHC(O)Me)-C₆H₃ 560 87 S(O)₂ 1 C₆H₅ 48388 S(O)₂ 0 2-NO₂-4-MeO—C₆H₃ 544 89 S(O)₂ 0 2-Me-5-NO₂—C₆H₃ 528 90 S(O)₂0 3-CO₂H—C₆H₄ 513 91 S(O)₂ 0 2,4,6-Me₃-C₆H₂ 511 92 S(O)₂ 0 Me 93 S(O)₂ 03,4-Cl₂—C₆H₃ 537 94 S(O)₂ 0 4-MeO—C₆H₄ 95 S(O)₂ 0 4-NHC(O)Me-C₆H₄ 526 96S(O)₂ 0 2-CF₃—C₆H₄ 537 97 S(O)₂ 0 (CH₂)₂CO₂Me 479 98 S(O)₂ 0 4-Me-C₆H₄483 99 S(O)₂ 0 4-CF₃—C₆H₄ 537 100 S(O)₂ 0 4-CN—C₆H₄ 494 101 S(O)₂ 03-NO₂-4-Me-C₆H₃ 528 102 S(O)₂ 0 1H-2-oxo-quinolin-6-yl 103 S(O)₂ 02-(NHCOMe)-4-methylthiazol-5-yl 547 104 S(O)₂ 0 Thien-2-yl 475 105 S(O)₂0 Quinolin-8-yl 106 S(O)₂ 0 2-OH-3,5-Cl₂—C₆H₂ 553 107 S(O)₂ 02-(CO₂Me)-C₆H₄ 527 108 S(O)₂ 0 2,5-(MeO)₂—C₆H₃ 529 109 S(O)₂ 0 phenyl469 110 S(O)₂ 0 2-Me-4-NO₂—C₆H₃ 528 111 S(O)₂ 05-(pyridin-2-yl)thien-2-yl 552 112 S(O)₂ 0 1,3-Me₂-5-Cl-pyrazol-4-yl 521113 S(O)₂ 0 3,5-Me₂-isoxazol-4-yl 488 114 S(O)₂ 0 2,3,6-Me₃-4-MeO—C₆H541 115 S(O)₂ 0 1-Me-imidazol-4-yl 473 116 S(O)₂ 0 2-MeO-5-Me-C₆H₃ 513117 S(O)₂ 0 5-(isoxazo1-3-yl)thien-2-yl 542 118 S(O)₂ 02-(CO₂Me)thien-3-yl 533 119 S(O)₂ 0 4-(1,1-dimethylprop-1-yl)-C₆H₄ 539120 S(O)₂ 0 1-(N-phthalimido)-ethyl 566 121 CH₂ 0 4-Me-C₆H₄ 433 122 CH₂0 4-(CO₂H)—C₆H₄ 463 123 CH₂ 0 2-(CO₂H)—C₆H₄ 463 124 CH₂ 04-(NHC(O)MC)—C₆H₄ 476 125 CH₂ 0 3-OH—C₆H₄ 435 126 CH₂ 0 4-MeO—C₆H₄ 449127 CH₂ 0 5-Me-fur-2-yl 423 128 CH₂ 0 2,5-F₂—C₆H₃ 455 129 CH₂ 05-NO₂-fur-2-y1 130 CH₂ 0 4-NO₂—C₆H₄ 131 CH₂ 0 4-iso-Pr—C₆H₄ 461 132 CH₂0 phenyl 419 133 CH₂ 0 2-(SO₃Na⁺)—C₆H₄ 498 134 CH₂ 0 4-F-C₆H₄ 437 135CH₂ 0 2,6-Cl₂—C₆H₃ 487 136 CH₂ 0 3,4-Cl₂—C₆H₃ 487 137 CH₂ 0 2,4-Cl₂—C₆H₃138 CH₂ 0 4-(OCH₂CO₂H)—C₆H₄ 493 139 CH₂ 0 Pyrid-2-yl 420 140 CH₂ 03-methylthien-2-yl 439 141 CH₂ 0 3-Cl—C₆H₄ 453 142 CH₂ 05-methylthien-2-yl 439 143 CH₂ 0 3-OH-4-MeO—C₆H₃ 465 144 CH₂ 03-NO₂-4-OH—C₆H₃ 480 145 CH₂ 0 Chromon-3-yl 146 CH₂ 01,3-Me₂-5-Cl-pyrazol-4-y1 471 147 CH₂ 0 3,4-F₂—C₆H₃ 455 148 CH₂ 04-Cl-pyrazol-3-yl 443 149 C(O) 1 4-S(O)₂Me-C₆H₄ 150 CH₂ 02,6-Cl₂-pyridin-4-yl 151 CH₂ 0 5-(4-NO₂—C₆H₄)-fur-2-yl 530 152 CH₂ 01-(4-methylbenzyl)-pyrazol-5-yl 153 CH₂ 0 Benzfur-2-yl 459 154 CH₂ 02-phenylimidazol-4-yl 485 155 CH₂ 0 5-ethylthien-2-yl 453 156 CH₂ 02-Cl-quinolin-3-yl 504 157 CH₂ 0 6-methylpyridin-2-yl 434 158 CH₂ 01-acetylindol-3-yl 500 159 CH₂ 0 6-formyl-pyridin-2-yl 448 160 CH₂ 0Quinolin-3-yl 161 CH₂ 0 5-(CH₂OC(O)CH₃)-fur-2-yl 162 CH₂ 0

529 163 CH₂ 0 Pyridin-4-yl 420 164 CH₂ 0 3-OH-4-NO₂—C₆H₃ 480 165 CH₂ 03,5-F₂—C₆H₃ 455 166 CH₂ 0 3-CF₃—C₆H₃ 487 167 CH₂ 0 2-F-6-Cl—C₆H₃ 471 168CH₂ 0 2-(tert-butyl)S—C₆H₄ 169 CH₂ 0 4-Et-C₆H₄ 447 170 CH₂ 03-CO₂H-4-OH—C₆H₄ 479 171 CH₂ 0 3-(OCH₂CO₂H)—C₆H₄ 493 172 CH₂ 02,3-methylenedioxyphenyl 463 173 CH₂ 0 Thiazol-2-yl 426 174 CH₂ 05-ethylfur-2-yl 437 175 CH₂ 0 Quinolin-2-yl 470 176 CH₂ 0 Quinolin-4-yl470 177 CH₂ 0 4-CH₂CH(CH₃)₂—C₆H₄ 475 178 CH₂ 0 3-MeO-4-OH-5-CO₂H—C₆H₂509 179 CH₂ 0 4-bromopyrazol-3-yl 180 CH₂ 0 2-(OCH₂CO₂H)-3-MeO—C₆H₃ 523181 CH₂ 0 4-(O(CH₂)₃N(CH₃)₂)—C₆H₄ 520 182 CH₂ 0 3-bromothien-2-yl 503183 CH₂ 0 3-phenoxythien-2-yl 517 184 CH₂ 0 5-methylthio-thien-2-yl 471185 CH₂ 0 1-methyl-4-bromopyrazol-3-yl 501 186 CH₂ 0 4-I—C₆H₄ 187 CH₂ 06,7-Me₂-chromon-3-yl 188 CH₂ 0 2-(OCH₂CO₂H)-5-NO₂—C₆H₄ 538 189 CH₂ 02-(2,6-dichlorobenzyloxy)phenyl 593 190 CH₂ 01-(4-chlorobenzyl)pyrazol-3-yl 533 191 CH₂ 0 4-iso-propoxy-C₆H₄ 477 192CH₂ 0 1-methylbenzimidazol-2-yl 473 193 CH₂ 0 3-Me-C₆H₄ 433 194 CH₂ 0Pyridin-3-yl 420 195 CH₂ 0 2,4-(MeO)₂-pyrimidin-5-yl 196 CH₂ 03-Cl-5-CF₃-pyridin-2-yl 522 197 CH₂ 0 2,4-Me₂-C₆H₃ 447 198 CH₂ 01-methylindol-3-yl 472 199 CH₂ 0 2-methyl-3-(CO₂Et)-fur-5-yl 200 CH₂ 01-Me-4-Cl-pyrazol-3-yl 457 201 C(O) 2 phenyl 461 202 C(O) 1 4-Br—C₆H₄525 203 C(O) 1 4-NH₂—C₆H₄ 462 204 C(O) 1 2-Br—C₆H₄ 525 205 C(O) I4-F-C₆H₄ 465 206 C(O) 1 2-CF₃—C₆H₄ 207 C(O) 1 3-Me-C₆H₄ 461 208 C(O) 12-Me-C₆H₄ 461 209 C(O) 1 3-Cl-4-OH—C₆H₃ 497 210 C(O) 39,10-dihydrophenanthren-2-yl 577 211 C(O) 1 2-NO₂—C₆H₄ 492 212 C(O) 12-Cl—C₆H₄ 481 213 C(O) 1 4-Cl—C₆H₄ 481 214 C(O) 1 2-benzyloxy-C₆H₄ 553215 C(O) 2 3,4-(OH)₂—C₆H₃ 493 216 C(O) 1 4-NO₂—C₆H₄ 492 217 C(O) 4Phenyl 489 218 C(O) 1 3,4-(MeO)₂—C₆H₃ 507 219 C(O) 1 4-EtO—C₆H₄ 491 220C(O) 1 3-F-4-OH—C₆H₃ 481 221 C(O) 3 Phenyl 475 222 C(O) 13,4-methylenedioxyphenyl 491 223 C(O) 3 4-MeO—C₆H₄ 505 224 C(O) 24-OH—C₆H₄ 477 225 C(O) 1 4-OH—C₆H₄ 463 226 C(O) 1 4-phenyl-C₆H₄ 523 227C(O) 1 3,4-Cl₂—C₆H₃ 515 228 C(O) 2 3-OH—C₆H₄ 477 229 C(O) 2 4-Me-C₆H₄475 230 C(O) 3 4-NO₂—C₆H₄ 520 231 C(O) 2 3,4-(MeO)₂—C₆H₃ 521 232 C(O) 34-Me-C₆H₄ 489 233 C(O) 2 C₆F₅ 551 234 C(O) 3 Dibenzothien-4-yl 581 235C(O) 1 4-Me-C₆H₄ 461 236 C(O) 2 4-SH—C₆H₄ 237 C(O) 1 4-CF₃O—C₆H₄ 531 238C(O) 1 4-CH₂Br—C₆H₄ 239 C(O) 3 3,4-(MeO)₂—C₆H₃ 535 240 C(O) 1 4-MeO—C₆H₄477 241 C(O) 1 4-(NMe₂)—C₆H₄ 490 242 C(O) 2 4-MeO—C₆H₄ 491 243 C(O) 22-MeO—C₆H₄ 491 244 C(O) 1 3,4,5-(MeO)₃—C₆H₂ 537 245 C(O) 23,4-methylenedioxyphenyl 505 246 C(O) 2 Dibenzothien-4-yl 247 C(O) 13-NH₂—C₆H₄ 462 248 C(O) I Naphth-1-yl 497 249 C(O) 1 3-MeO-4-OH—C₆H₃ 493250 C(O) 1 Naphth-2-yl 251 C(O) 13-(1-allyl-6-bromonaphth-2-yloxy)CH₂—C₆H₄ 721 252 C(O) 1 4-NO₂—C₆H₄ 253C(O) 1 3-F-4-MeO—C₆H₃ 495 254 C(O) 4 3-Me-C₆H₄ 503 255 C(O) 1 3-OH—C₆H₄463 256 C(O) 1 4-benzyloxy-C₆H₄ 553 257 C(O) 1 4-(3-NO₂—C₆H₄—C₆H₄ 568258 C(O) 1 2,5-(Me)₂—C₆H₃ 475 259 C(O) 1 4-I—C₆H₄ 573 260 C(O) I4-(4-(1-Me-2-OH-4-(pyridin-3-yl)-butoxy)- 702 C₆H₄)-C₆H₄ 261 C(O) 13-Br—C₆H₄ 525 262 C(O) 2 3-(n-Pr)—C₆H₄ 503 263 C(O) 14-(4-NO₂—C₆H₄CH₂O)—C₆H₄ 598 264 C(O) 1 2,5-(OH)₂—C₆H₃ 265 C(O) 12-Me-3-NO₂—C₆H₃ 506 266 C(O) 1 4-(CH₂NHCO₂CH₂(fluoren-9-yl))-C₆H₄ 267C(O) 1 3-OH-4-MeO—C₆H₄ 493 268 C(O) 1 3-F-C₆H₄ 465 269 C(O) 1 2-F-C₆H₄465 270 C(O) 1 3,5-(MeO)₂—C₆H₃ 507 271 C(O) 1 3-Cl—C₆H₄ 481 272 C(O) 1Phenyl 447 273 C(O) 1 3,5-Me₂—C₆H₃ 475 274 C(O) 2 3-MeO—C₆H₄ 491 275C(O) 1 2,4-F₂—C₆H₃ 483 276 C(O) 1 2-MeO—C₆H₄ 477 277 C(O) 1 3,4-F₂—C₆H₃483 278 C(O) 1 3,5-F₂—C₆H₃ 483 279 C(O) 5 phenyl 503 280 S(O)₂ 05-(pyridin-2-yl)-thien-2-yl 281 C(O) 0 3-S(O)₂Me-C₆H₄ 511 282 C(O) 03-MeO-4-NH₂—C₆H₃ 283 C(O) 0 3-MeO-4-F—C₆H₃ 481 284 C(O) 0Benzthiazol-6-yl 490 285 C(O) 0 3-MeO—C₆H₄ 477 286 C(O) 03-C₆H₅S(O)—C₆H₄ 557 287 C(O) 0 4-S(O)₂Me-C₆H₄ 511 288 C(O) 02,4-Cl₂—C₆H₃ 501 289 C(O) 0 4-NO₂—C₆H₄ 478 290 C(O) 0 3-CN—C₆H₄ 458 291C(O) 0 4-MeO—C₆H₄ 463 292 C(O) 0 4-CN—C₆H₄ 458 293 C(O) 0 2-S(O)₂Me-C₆H₄511 294 C(O) 0 2-Cl-4-S(O)₂Me-C₆H₃ 545 295 C(O) 03-(C₆H₅S(O)₂CH₂)-4-NO₂—C₆H₃ 632 296 C(O) 0 2-(C₆H₅S(O)₂CH₂)—C₆H₄ 297C(O) 0 Benzo[1,2,3]thiadiazol-5-yl 491 298 C(O) 0 4-EtS—C₆H₄ 493 299C(O) 0 3-CF₃S—C₆H₄ 533 300 C(O) 0 4-CF₃S—C₆H₄ 533 301 C(O) 03-CH₃C(O)NH—C₆H₄ 490 302 C(O) 0 3-CH₃-4-NH₂—C₆H₃ 462 303 C(O) 0Indol-7-yl 472 304 C(O) 0 3-CH₃CH₂O-4-CH₃O—C₆H₃ 507 305 C(O) 04-(2,5-dihydropyrrol-1-yl)-C₆H₄ 500 306 C(O) 1 3-Br-pyridin-5-yl 526 307C(O) 1 1-methyl-imidazol-4-yl 451 308 C(O) 1 5-OH-indol-3-yl 502 309C(O) 1 Thiophen-3-yl 453 310 C(O) 0 3-CH₃CH₂S(O)₂—C₆H₄ 525 311 C(O) 03-CH₃(CH₂)₂S(O)₂—C₆H₄ 539 312 C(O) 0 3-(CH₃)₂CHCH₂S(O)₂—C₆H₄ 553 313C(O) 0 3,4-(CH₃S(O)₂)₂—C₆H₃ 589 314 C(O) 0 3-CH₃CH₂O-4-NH₂—C₆H₃ 492 315C(O) 1 Pyridin-4-yl 448 316 C(O) 0 2-CH₃S(O)₂CH₂—C₆H₄ 525 317 C(O) 02-NH₂—C₆H₄ 448 318 C(O) 0 1-acetyl-indol-3-yl 319 C(O) 0 Indol-3-yl 320C(O) 0 3-NH₂(CH₂)₂O—C₆H₄ 321 C(O) 0 3-CH₃NHS(O)₂—C₆H₄ 322 C(O) 03-NH₂S(O)₂—C₆H₄ 323 C(O) 0 3-CH₃O(CH₂)₂O—C₆H₄ 324 C(O) 03-(CH₃)₃COC(O)NH(CH₂)₂O—C₆H₄ 325 C(O) 0 1,2,3-benzothiadiazol-6-yl 326C(O) 0 3-HOC(O)CH₂O—C₆H₄ 327 C(O) 0 2-CH₃S(O)₂-3-CN-thiophen-5-yl 542328 C(O) 0 3-CH₃S(O)₂-4-NH₂—C₆H₃ 526 329 C(O) 02-CH₃S(O)₂-3-NH₂C(O)-thiophen-5-yl 560 330 C(O) 0 3-CF₃O—C₆H₄ 501 331C(O) 0 2-(CH₃)₂CHS(O)₂-3-NH₂-thiophen-4-yl 560 332 C(O) 02-CH₃S(O)₂-thiophen-5-yl 517 333 C(O) 03-CH₃-5-(4-CH₃-1,2,3-thiadiazol-5-yl)-isoxazol-4-yl 536 334 C(O) 03-Cl-5-CF₃-pyridin-2-yl 536 335 C(O) 1 4-CF₃O—C₆H₄ 531 336 C(O) 01H-benzotriazol-5-yl 474 337 C(O) 0 4-CH₃S(O)₂CH₂—C₆H₄ 525 338 C(O) 03-CH₃S(O)₂CH₂—C₆H₄ 525 339 C(O) 0 2-CN—C₆H₄ 458 340 C(O) 0 Quinolin-6-yl484 341 C(O) 0 Quinoxalin-6-yl 485 342 C(O) 03-NH₂-4-CH₃S(O)₂-thiophen-2-yl 532 343 C(O) 0

566 344 C(O) 0

345 C(O) 0 3-CF₃O—C₆H₄ 517 346 C(O) 0 2,5-(CH₃O)₂—C₆H₃ 493 347 C(O) 01-(CH₃)₂CH-benzotnazol-5-yl 348 C(O) 0

349 C(O) 0 3-HO(CH₂)₂S(O)₂—C₆H₄ 350 C(O) 0 2-HO(CH₂)₂S(O)₂—C₆H₄ 351 C(O)0 3-cyclopropylCH₂S(O)₂—C₆H₄ 352 C(O) 0 2-CH₃S(O)₂NH—C₆H₄ 526 353 C(O) 0(CF₃)(MeO)(C₆H₅)C 545 354 C(O) 0 (C₆H₅)₂CH 523 355 C(O) 0(4-Cl—C₆H₄)(CH₃)₂C 509 356 C(O) 0 (C₆H₅)(cyclohexyl)CH 529 357 C(O) 0(4-F—C₆H₄)(CH₃)CH 479 358 C(O) 1 3,4-methylenedioxy-C₆H₄ 491 359 C(O) 0(C₆H₅)(cyclopentyl)CH 515 360 C(O) 0 ((CH₃)(CH₃CH₂)CH)(C₆H₅)CH 503 361C(O) 0 1-phenyl-cyclopentyl 501 362 C(O) 0 1-(4-Cl—C₆H₄)cyclopentyl 535363 C(O) 0 1-phenyl-cyclopropyl 473 364 C(O) 0 1-phenyl-cyclohexyl 515365 C(O) 0 (C₆H₅)(cyclohexyl)C(OH) 545 366 C(O) 0 ((CH₃)₂CH)(C₆H₅)CH 489367 C(O) 1 pyrid-3-yl 448 368 C(O) 1 pyrid-2-yl 448 369 C(O) 15-Br-pyrid-3-yl 526 370 C(O) 1 2,4-(MeO)₂—C₆H₃ 507 371 C(O) 14-benzyloxy-phenyl 553 372 C(O) 1 3-benzyloxy-phenyl 553 373 C(O) 1

549 374 C(O) 0 2-EtO—C₆H₄ 491 375 C(O) 0

549 376 C(O) 1 4-n-butoxyphenyl 519 377 C(O) 1 indol-1-yl 486 378 C(O) 12-NO₂-phenyl 492 379 C(O) 1 thien-2-yl 453 380 C(O) 1 3-Cl-4-OH-phenyl497 381 C(O) 1 2-Br-phenyl 525 382 C(O) 1 3-Br-phenyl 525 383 C(O) 13,5-F₂-phenyl 483 384 C(O) 1 3-aminophenyl 462 385 C(O) 13,4-(OH)₂-phenyl 479 386 C(O) 1 2,5-(MeO)₂-phenyl 507 387 C(O) 14-Me-phenyl 461 388 C(O) 0 5-(4-Cl—C₆H₄)-tetrazol-2-yl 549 389 C(O) 14-MeS(O)₂-phenyl 525 390 C(O) 1 4-F-phenyl 465 391 C(O) 15-Cl-benzo[b]thiophen-3-yl 537 392 C(O) 1 4-CF₃O-phenyl 531 393 C(O) 13-Me-5-Cl-benzo[b]thiophen-2-yl 551 394 C(O) 1 2-nitrophenyl 492 395C(O) 1 4-Cl-5-Me-3-NO₂-pyrazol-1-yl 530 396 C(O) 12-CF₃-benzimidazol-1-yl 555 397 C(O) 1 2-EtS-benzimidazol-1-yl 547 398C(O) 1 2-Me-4-(thien-2-yl)-thiazol-5-yl 550 399 C(O) 14-Br-3,5-Me₂-pyrazol-1-yl 543 400 C(O) 1 5-Me-3,4-(NO₂)₂-pyrazol-1-yl541 401 C(O) 1 4-(3-methyl-butoxy)-phenyl 533 402 C(O) 12-tert-butylthio-phenyl 535 403 C(O) 1 4-Cl-3,5-Me₂-pyrazol-1-yl 499 404C(O) 1

535 405 C(O) 1 2,4-(NO₂)₂-imidazol-1-yl 527 406 C(O) 13,5-Me₂-pyrazol-1-yl 465 407 C(O) 1 4-n-hexyl-phenyl 531 408 C(O) 02-NH₂-pyrid-5-yl 449 409 C(O) 0 Pyrid-2-yl 434 410 C(O) 02-EtS-pyrid-3-yl 494 411 C(O) 0 2-OH-quinolin-4-yl 500 412 C(O) 02-OH-pyrid-5-yl 450 413 C(O) 0 2,6-(MeO)₂-pyrid-3-yl 494 414 C(O) 02-(imidazol-1-yl)-pyrid-5-yl 500 415 C(O) 0 2-CO₂CH₃-pyrid-3-yl 492 416C(O) 0 2-Me-pyrid-5-yl 448 417 C(O) 0 Quinolin-2-yl 484 418 C(O) 06-Me-pyrid-2-yl 448 419 C(O) 0 2-OH-6-Me-pyrid-3-yl 464 420 C(O) 08-OH-quinolin-2-yl 500 421 C(O) 1 3-F-phenyl 465 422 C(O) 0Imidazo[1,2-a]pyrid-2-yl 473 423 C(O) 0 2-methyl-[1,8]naphthyridin-3-yl499 424 C(O) 0 [1,6]naphthyridin-2-yl 485 425 C(O) 02-methyl-[1,6]naphthyridin-3-yl 499 426 C(O) 01-methyl-1H-pyrid-2-one-5-yl 464 427 C(O) 0 Quinolin-4-yl 484 428 C(O) 0Quinolin-6-yl 484 429 C(O) 0 3-(CH₃(CH₂)₂S(O)₂)—C₆H₄ 539 430 C(O) 05-((pyrid-2-yl)SCH₂)fur-2-y1 546 431 C(O) 0 2-Me-3-OH-quinolin-4-yl 514432 C(O) 0 (pyrid-2-yl)CH═CH 460 433 C(O) 0 (2-EtS-pyrid-5-yl)CH═CH 520434 C(O) 0 1-(5-CF₃-pyrid-2-yl)-piperidin-4-yl 585 435 C(O) 02,7-Me₂-imidazo1,2-a]Pyrid-3-yl 501 436 C(O) 0(5-CF₃-pyrid-2-yl)SO₂CH(CH₃) 594 437 C(O) 1 3-(pyrid-2-yl)pyrazol-l-yl514 438 C(O) 0 3-NH₂-4-CH₃O—C₆H₃ 478 439 C(O) 0 2,5-(CH₃O)₂—C₆H₃ 493 440C(O) 0 3-F-4-CH₃—C₆H₃ 465 441 C(O) 0 3-phenyl-5-CH₃-isoxazol-4-yl 514442 C(O) 0 1-phenyl-5-CH₃-pyrazol-4-yl 513 443 C(O) 0 3-CF₃O—C₆H₄ 517444 C(O) 0 2-CH₃O-5-Cl—C₆H₃ 497 445 C(O) 0 2-CH₃-3-F—C₆H₃ 465 446 C(O) 02-(2-phenyl-thiazol-4-yl)phenyl 592 447 C(O) 0 3,4-methylenedioxyphenyl477 448 C(O) 0 5-phenyl-oxazol-4-yl 500 449 C(O) 0 1H-indazol-3-yl 473450 C(O) 0 1-CH₃-indol-3-yl 486 451 C(O) 0 1-iso-propyl-benztriazol-5-yl516 452 C(O) 0

473 453 C(O) 0 2-CH₃-5-F—C₆H₃ 465 454 C(O) 0 3-CF₃O-4-NH₂—C₆H₃ 532 455C(O) 0 3-CH₃-5-CF₃-isoxazol-4-yl 506 456 C(O) 0(1,2,4-triazol-1-yl)C(CH₃)₂ 466 457 C(O) 0 2-phenyl-thiazol-4-yl 516 458C(O) 0 2-CH₃-4-CF₃-thiazol-5-yl 522 459 C(O) 0

529 460 C(O) 0

558 461 C(O) 0 3-F-4-CF₃—C₆H₃ 519 462 C(O) 0

501 463 C(O) 0 2-CH₃-benzimidazol-5-yl 487 464 C(O) 1

534 465 C(O) 0 3-iso-propoxy-4-CH₃O—C₆H₃ 521 466 C(O) 0

519 467 C(O) 0

534 468 C(O) 0 2-CH₃O-5-F—C₆H₃ 481 469 C(O) 0 3-CH₃CH₂O—C₆H₄ 470 C(O) 02-(C₆H₅S(O)CH₂)—C₆H₄ 471 C(O) 0 1H-indol-3-yl 472 472 S(O)₂ 1 2-NO₂—C₆H₄528 473 S(O)₂ 0 2-CN—C₆H₄ 494 474 C(O) 0 3-CH₃S(O)₂—C₆H₄ 511 475 C(O) 03-S(O)₂NHCH₃—C₆H₄ 526 476 C(O) 0 Benzo[1,2,3]thiadiazol-6-yl 491 477C(O) 0 3-CH₃O(CH₂)₂O—C₆H₄ 507 478 C(O) 0 3,4-(CH₃S(O)₂)₂—C₆H₃ 589 479C(O) 0 3-CH₃O—C₆H₄ 463 480 C(O) 0 3-CN—C₆H₄ 458 481 C(O) 0 4-F—C₆H₄ 451482 C(O) 0 3-CH₃O-4-F—C₆H₃ 481 483 C(O) 0 3H-benzothiazol-2-one-6-yl 506484 C(O) 0 2-CH₃S(O)₂-thien-5-yl 517 485 C(O) 0 3-CH₃-4-NH₂—C₆H₃ 462 486C(O) 0 Benzothiazol-6-yl 490 487 C(O) 0 1H-5-CH3S(O)₂-indol-2-yl 550 488C(O) 0 1H-5-CH₃O-indol-2-yl 502 489 C(O) 0 1H-indol-4-yl 472 490 C(O) 01H-Benzimidazol-5-yl 473 491 C(O) 0 3,4-methylenedioxyphenyl 477 492C(O) 0 1H-5-Cl-indol-2-yl 506 493 C(O) 0 lH-5-OH-indol-2-yl 488 494 C(O)0

558 495 C(O) 0 3,4-difluoromethylenedioxyphenyl 513 496 C(O) 02-(pyrazol-1-yl)-pyridin-5-yl 500 497 C(O) 0 4-CF₃-pyridin-3-yl 502 498C(O) 0

576 499 C(O) 0

459 500 C(O) 0 3-n-propoxy-pyridin-2-yl 492 501 C(O) 12-(2,4-F₂—C₆H₃)thiazol-4-yl 566 502 C(O) 0 1H-indol-2-yl 472 503 C(O) 12-phenyl-5-CH₃-thiazol-4-yl 544 504 C(O) 0 2-S(O)₂NH₂-4-Cl—C₆H₃ 546 505C(O) 0 2-CN—C₆H₄ 458 506 C(O) 0 1H-indol-7-yl 472 507 C(O) 01H-5-F-indol-2-yl 490 508 C(O) 0 1 H-pyrazol-4-yl 423 509 C(O) 01-CH₃-pyrrol-2-yl 436 511 C(O) 0 3-pyrrol-1-yl)-4-CN-thien-2-yl 529 512C(O) 0 3-CH₃O-4-NH₂—C₆H₃ 478 513 C(O)C(O) 0 1H-indol-3-yl 500 514 C(O) 04-(pyrrol-1-yl)phenyl 498 515 C(O) 0 1-CH₃-indol-2-yl 486 516 C(O) 11H-indol-3-yl 486 517 C(O) 1 1H-5-CH₃O-indol-3-yl 516 518 C(O) 02-(pyridin-2-yl)-thien-5-yl 516 519 C(O) 0 1H-5-F-indol-2-yl 490 520C(O) 1 3-CH₃-benzo[b]thiophen-2-yl 517 521 C(O) 13,5-(CH₃)₂-4-NO₂-pyrazol-1-yl 510 522 C(O) 02-CF₃-[1,6]-naphthyridin-3-yl 553 523 C(O) 02-(1-CH₃-5-CF₃-pyrazol-3-yl)-thien-5-yl 587 524 C(O) 0

638 525 C(O) 1 3-Cl—C₆H₄ 481 526 C(O) 1 5-CH₃-3-NO₂-pyrazol-1-yl 496 527C(O) 1 2-CN—C₆H₄ 472 528 C(O) 0 Quinoxalin-2-yl 485 529 C(O) 0Pyrazin-2-yl 435 530 C(O) 0

549 531 C(O) 0 1-tert-butyl-3-CH₃-pyrazol-5-yl 493 532 C(O) 02-SH-pyridin-3-yl 466 533 C(O) 0 Quinolin-3-yl 484 534 C(O) 0

543 535 C(O) 0 2-ethoxy-phenyl 477 536 C(O) 1 4-NO₂-imidazol-1-yl 482537 C(O) 0 4-CH₃O-quinolin-2-yl 514 538 C(O) 0 2-SCH₂CH═CH₂-pyridin-3-yl506 539 C(O) 0 1-iso-propyl-benztriazol-5-yl 516 540 C(O) 0[1,8]-naphthyridin-2-yl 485 541 C(O) 1 2-CH₃-4-phenyl-thiazol-5-yl 544542 C(O) 0 1-CH₃-indol-2-yl 486 543 C(O) 0 2-phenoxy-pyridin-5-yl-CH═CH552 544 C(O) 1 3,4-Cl₂—C₆H₃ 515 545 C(O) 02-S(O)₂CH₃-3-CN-6-CH₃-pyridin-4-yl 551 546 C(O) 03H-Benzothiazol-2-one-6-yl 506 547 C(O) 0 2-CH₃O-pyridin-3-yl 464 548C(O) 0 Isoquinolin-1-yl 484 549 C(O) 1 4-OH—C₆H₄ 463 550 C(O) 0Quinolin-8-yl 484 551 C(O) 0 2-CN—C₆H₄ 458 552 C(O) 02-CF₃-[1,8]-naphthyridin-3-yl 553 553 C(O) 0 2-CO₂CH₃-pyridin-6-yl 492554 C(O) 0 Isoquinolin-3-yl 484 555 C(O) 0 3-CH₂S(O)₂CH₃—C₆H₄ 525 556C(O) 0 2-ethoxy-pyridin-3-yl 478 557 C(O) 1

516 558 C(O) 0 2-CH₃O-pyridin-5-yl 464 559 C(O) 0 Indan-1-one-3-yl 487560 C(O) 1 3-NO₂-[1,2,4]-triazol-l-yl 483 561 C(O) 01-(CH₃)₂CH-benzotriazol-5-yl 516 562 C(O) 1 1H-2-CH₃-indol-3-yl 500 563C(O) 0 3,5-(CH₃)₂-isoxazol-4-yl 452 564 C(O) 0 1,5-(CH₃)₂-pyrazol-4-yl451 565 C(O) 0 Quinoxalin-6-yl 485 566 C(O) 0 3-NO₂[1,2,4]triazol-1-yl483 567 C(O) 0 1H-indol-3-yl-CH═CH 498 568 C(O) 14-(pyridin-2-yl)-pyrimidin-2-yl-S 558 569 C(O) 0 3-S(O)₂NH₂—C₆H₄ 512 570C(O) 1 1H-5-OH-indol-3-yl 502 571 C(O) 0 4-CH₂S(O)₂CH₃—C₆H₄ 525 572 C(O)0

500 573 C(O) 0 Isoxazol-5-yl 424 574 C(O) 1 1-CH₃-4-NO₂-pyrazol-5-yl 496575 C(O) 0

645 576 C(O) 0 3-ethoxy-4-amino-phenyl 492 577 C(O) 11,4-(CH₃)₂-3-CO₂H-pyrrol-2-yl 508 578 C(O) 0

473 579 C(O) 0

491 580 C(O) 0 2-OH-quinolin-4-yl 500 582 C(O) 0 3-amino-phenyl 448 583C(O) 0 3-NHS(O)₂CH₃—C₆H₄ 526 584 C(O) 0 3-C(CH₃)₃OC(O)NH(CH₂)₂O—C₆H₄ 592585 C(O) 0 3-HO₂CCH₂O—C₆H₄ 507 586 C(O) 0 3-H₂N(CH₂)₂O—C₆H₄ 492 587 C(O)0 2-NHS(O)₂CH₃—C₆H₄ 526 588 C(O) 0 2-S(O)₂CH₂cyclopropyl-C₆H₄ 551 589C(O) 0 3-S(O)₂N(CH₃)₂—C₆H₄ 540 590 C(O) 0 3-NO₂-5-S(O)₂OH₃—C₆H₃ 556 591C(O) 0 3-NH₂-5-S(O)₂OH₃—C₆H₃ 526 592 C(O) 0 1-S(O)₂OH₃-indol-3-yl 593C(O) 0 3-CN-5-S(O)₂CH₃—C₆H₃ 536 594 C(O) 0 1H-5-S(O)₂CH₃-indol-3-yl 550595 C(O) 0 CH(Phenyl)(CH₂piperazin-1-yl) 545 596 C(O) 1

518 597 C(O) 0 3-S(O)₂NH₂-4-Cl—C₆H₃ 546 598 C(O) 0

474 599 C(O) 0

487 600 C(O) 0

507 601 C(O) 0

487 602 C(O) 0 2-NO₂-5-S(O)₂CH₃—C₆H₃ 603 C(O) 0 2-NH₂-5-S(O)₂CH₃—C₆H₃

Examples of compounds of formula (Ic) are listed in Table II below.

TABLE II Compound m p T R³ 1 1 1 C(O) 3-MeO-4-NH₂—C₆H₃ 2 0 2 C(O)3-MeO-4-NH₂—C₆H₃ 3 1 1 S(O)₂ 5-(pyridin-2-yl)-thien-2-yl 4 0 1 C(O)3-MeO-4-NH₂—C₆H₃ 5 1 1 C(O) 3H-benzthiazol-2-one-6-yl 6 1 1 C(O)

7 1 1 C(O) [1,8]naphthyridin-2-yl 8 1 1 C(O)

Examples of compounds of formula (Id) are listed in Table III below

TABLE III Compound R³ 1 4-F—C₆H₄ 2 Phenyl 3 3,4-F₂—C₆H₃

Examples of compounds of formula (If) are listed in Table IV below.

TABLE IV Compound R¹ t s n R³ 1 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 23-Cl-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 3 3-F-4-Cl—C₆H₃ 1 0 03-CH₃S(O)₂—C₆H₄ 4 3-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 52-CH₃O-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 6 4-CH₃O—C₆H₄ 1 0 03-CH₃S(O)₂—C₆H₄ 7 4-CH₃O—C₆H₄ 0 0 0 3-CH₃S(O)₂—C₆H₄ 8 4-Cl—C₆H₄ 0 0 03-CH₃S(O)₂—C₆H₄ 9 3,4-Cl₂-C₆H₃ 0 0 0 3-CH₃S(O)₂—C₆H₄ 10 4-CN-C₆H₄ 0 0 03-CH₃S(O)₂—C₆H₄ 11 3,4-F₂—C₆H₃ 0 0 0 3-CH₃S(O)₂—C₆H₄ 12 4-F—C₆H₄ 0 0 03-CH₃S(O)₂—C₆H₄ 13 4-CH₃C(O)NH—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 14 4-CH₃—C₆H₄1 0 0 3-CH₃S(O)₂—C₆H₄ 15 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 164-Cl—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 17 4-F—C₆H₄ 1 0 0 3-CH₃S(O)₂—C₆H₄ 182,4-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 19 2-Cl-4-F—C₆H₃ 1 0 03-CH₃S(O)₂—C₆H₄ 20 2,4-F₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 21 2-F-4-Cl—C₆H₃ 10 0 3-CH₃S(O)₂—C₆H₄ 22 2-CH₃-4-F—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 232-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 24 3-F-4-Cl—C₆H₃ 1 0 03-CH₃O-4-NH₂—C₆H₃ 25 2-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 262-CH₃O-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 27 4-CH₃O—C₆H₄ 1 0 03-CH₃O-4-NH₂—C₆H₃ 28 3-Cl-4-F—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 29 4-CH₃—C₆H₄1 0 0 3-CH₃O-4-NH₂—C₆H₃ 30 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 314-Cl—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 32 4-F—C₆H₄ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 332,4-Cl₂—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 34 2-Cl-4-F—C₆H₃ 1 0 03-CH₃O-4-NH₂—C₆H₃ 35 2,4-F₂—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 362-F-4-Cl—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 37 2-CH₃-4-F—C₆H₃ 1 0 03-CH₃O-4-NH₂—C₆H₃ 38 2-CH₃-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 393-F-4-Cl—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 40 2-CH₃O-4-Cl—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 41 2-CH₃O-4-F—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 42 4-CH₃O—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl43 3-Cl-4-F—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 44 4-CH₃—C₆H₄ 1 0 01,2,3-benzthiadiazol-5-yl 45 3-Cl-4-CH₃—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 46 4-Cl—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl47 4-F—C₆H₄ 1 0 0 1,2,3-benzthiadiazol-5-yl 48 2,4-Cl₂—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 49 2-Cl-4-F—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 50 2,4-F₂—C₆H₃ 1 0 0 1,2,3-benzthiadiazol-5-yl 51 2-F-4-Cl—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 52 2-CH₃-4-F—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 53 3,4-Cl₂—C₆H₃ 1 1 0 3-CN—C₆H₄ 543,4-Cl₂—C₆H₃ 1 1 0 3-CH₃S(O)₂—C₆H₄ 55 2-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃S(O)₂—C₆H₄ 56 3-Cl-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 57 3-F-4-Cl—C₆H₃1 0 0 2-CH₃S(O)₂—C₆H₄ 58 3-CH₃O-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 592-CH₃O-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 60 4-CH₃O—C₆H₄ 1 0 02-CH₃S(O)₂—C₆H₄ 61 4-CH₃C(O)NH—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 62 4-CH₃—C₆H₄1 0 0 2-CH₃S(O)₂—C₆H₄ 63 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 644-Cl—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 65 4-F—C₆H₄ 1 0 0 2-CH₃S(O)₂—C₆H₄ 662,4-Cl₂—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 67 2-Cl-4-F—C₆H₃ 1 0 02-CH₃S(O)₂—C₆H₄ 68 2,4-F₂—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 69 2-F-4-Cl—C₆H₃ 10 0 2-CH₃S(O)₂—C₆H₄ 70 2-CH₃-4-F—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₄H₄ 712-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 72 3-Cl-4-F—C₆H₃ 1 0 02-CH₃S(O)₂-thiophen-5-yl 73 3-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl74 3-CH₃O-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 75 2-CH₃O-4-F—C₆H₃ 10 0 2-CH₃S(O)₂-thiophen-5-yl 76 4-CH₃O—C₆H₄ 1 0 02-CH₃S(O)₂-thiophen-5-yl 77 4-CH₃C(O)NH—C₆H₄ 1 0 02-CH₃S(O)₂-thiophen-5-yl 78 4-CH₃—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 793-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 80 4-Cl—C₆H₄ 1 0 02-CH₃S(O)₂-thiophen-5-yl 81 4-F—C₆H₄ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 822,4-Cl₂—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 83 2-Cl-4-F—C₆H₃ 1 0 02-CH₃S(O)₂-thiophen-5-yl 84 2,4-F₂—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl85 2-F-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 86 2-CH₃-4-F—C₆H₃ 1 0 02-CH₃S(O)₂-thiophen-5-yl 87 3-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 883-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃O-4-NH₂—C₆H₃ 89 3-CH₃-4-Cl—C₆H₃ 1 0 01,2,3-benzthiadiazol-5-yl 90 3-Cl-4-CH₃—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 913-Cl-4-CH₃—C₆H₃ 1 0 0 2-CH₃S(O)₂-thiophen-5-yl 92 2-CH₃-4-Cl—C₆H₃ 1 0 0Quinolin-6-yl 93 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-(CH₃O(CH₂)₂O)—C₆H₄ 942-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-(CH₃S(O)₂)₂—C₆H₃ 95 2-CH₃-4-Cl—C₆H₃ 1 0 03-CH₃O—C₆H₄ 96 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CN—C₆H₄ 97 2-CH₃-4-Cl—C₆H₃ 1 0 04-F—C₆H₄ 98 2-CH₃-4-Cl—C₆H₃ 1 0 0 Indol-7-yl 99 2-CH₃-4-Cl—C₆H₃ 1 0 05-CH₃S(O)₂-indol-2-yl 100 2-CH₃-4-Cl—C₆H₃ 1 0 0 Benzimidazol-5-yl 1012-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxy-C₆H₃ 102 2-CH₃-4-Cl—C₆H₃ 1 0 05-F-indol-2-yl 103 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-CF₃-thieno[3,2-bpyridin-6-yl104 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl 1053-CH₃-4-Cl—C₆H₃ 1 0 0 Quinolin-6-yl 106 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CN—C₆H₄107 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-(CH₃O(CH₂)₂O)-C₆H₄ 108 3-CH₃-4-Cl—C₆H₃ 1 0 03,4-(CH₃S(O)₂)₂—C₆H₃ 109 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O—C₆H₄ 1103-CH₃-4-Cl—C₆H₃ 1 0 0 3-CN—C₆H₄ 111 3-CH₃-4-Cl—C₆H₃ 1 0 0 4-F—C₆H₄ 1123-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃S(O)₂-thien-2-yl 113 3-CH₃-4-Cl—C₆H₃ 1 0 0Indol-7-yl 114 3-CH₃-4-Cl—C₆H₃ 1 0 0 5-CH₃S(O)₂-indol-2-yl 1153-CH₃-4-Cl—C₆H₃ 1 0 0 3-EtO-4-NH₂—C₆H₃ 116 3-CH₃-4-Cl—C₆H₃ 1 0 05-CH₃O-indol-2-yl 117 3-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxy-C₆H₃ 1183-CH₃-4-Cl—C₆H₃ 1 0 0 5-F-indol-2-yl 119 3-CH₃-4-Cl—C₆H₃ 1 0 05-CF₃-thieno[3,2-b]pyridin-6-yl 120 3-CH₃-4-Cl—C₆H₃ 1 0 02-(pyrazol-1-yl)-pyridin-5-yl 121 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-NH₂-4-MeO—C₆H₃122 2-CH₃-4-Cl—C₆H₃ 1 0 0 Pyrazin-2-yl 123 2-CH₃-4-Cl—C₆H₃ 1 0 03-phenyl-5-Me-isoxazol-4-yl 124 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O—C₆H₄ 1252-CH₃-4-Cl—C₆H₃ 1 0 0 2-MeO-5-Cl—C₆H₃ 126 2-CH₃-4-Cl—C₆H₃ 1 0 02-Me-3-F—C₆H₃ 127 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-EtO—C₆H₄ 128 2-CH₃-4-Cl—C₆H₃ 10 0 5-phenyl-oxazol-4-yl 129 2-CH₃-4-Cl—C₆H₃ 1 0 0 5-F-1H-indol-2-yl 1302-CH₃-4-Cl—C₆H₃ 1 0 0 2H-isoquinolin-1-one-4-yl 131 2-CH₃-4-Cl—C₆H₃ 1 00 3H-benzothiazol-2-one-6-yl 132 2-CH₃-4-Cl—C₆H₃ 1 0 0Bicyclo[4.2.0]octa-1,3,5-trien-7-yl 133 2-CH₃-4-Cl—C₆H₃ 1 0 01-iso-propylbenztriazol-5-yl 134 2-CH₃-4-Cl—C₆H₃ 1 0 01-phenylcyclopropyl 135 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-NH₂S(O)₂-4-Cl—C₆H₃ 1362-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O-4-NH₂—C₆H₃ 137 2-CH₃-4-Cl—C₆H₃ 1 0 03-(pyrrol-1-yl)-4-CN-thien-2-yl 138 2-CH₃-4-Cl—C₆H₃ 1 0 02-(CH₃O(CH₂)₂0)-5-NH₂—C₆H₃ 139 2-CH₃-4-Cl—C₆H₃ 1 0 01-(1-CH₃-5-CF₃-pyrazol-3-yl)-thien-5-yl 140 2-CH₃-4-Cl—C₆H₃ 1 0 0(1,2,4-triazol-1-yl)C(CH₃)₂ 141 2-CH₃-4-Cl—C₆H₃ 1 0 02-phenyl-thiazol-4-yl 142 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-4-CF₃-thiazol-5-yl143 2-CH₃-4-Cl—C₆H₃ 1 0 0 [1,8]-naphthyridin-2-yl 144 2-CH₃-4-Cl—C₆H₃ 10 0

145 2-CH₃-4-Cl—C₆H₃ 1 0 0

146 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CF₃-C₆H₃ 147 2-CH₃-4-Cl—C₆H₃ 1 0 0

148 2-CH₃-4-Cl—C₆H₃ 1 0 0

149 2-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃-benzimidazol-5-yl 150 2-CH₃-4-Cl—C₆H₃ 10 1

151 2-CH₃-4-Cl—C₆H₃ 1 0 0

152 2-CH₃-4-Cl—C₆H₃ 1 0 0 1,5-dimethyl-pyrazol-3-yl 153 2-CH₃-4-Cl—C₆H₃1 0 0 2-CH₃O-5-F—C₆H₃ 154 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-NH₂-4-CH₃O—C₆H₃ 1553-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 156 3-CH₃-4-Cl—C₆H₃ 1 0 03-F-4-CH₃—C₆H₃ 157 3-CH₃-4-Cl—C₆H₃ 1 0 0 Pyrazin-2-yl 1583-CH₃-4-Cl—C₆H₃ 1 0 0 3-phenyl-5-CH₃-isoxazol-4-yl 159 3-CH₃-4-Cl—C₆H₃ 10 0 1-phenyl-5-CH₃-pyrazol-4-yl 160 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O—C₆H₄161 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-5-Cl—C₆H₃ 162 3-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃-3-F—C₆H₃ 163 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃CH₂O—C₆H₄ 1643-CH₃-4-Cl—C₆H₃ 1 0 0 2-(2-phenyl-thiazol-4-yl)-Phenyl 1653-CH₃-4-Cl—C₆H₃ 1 0 0

166 3-CH₃-4-Cl—C₆H₃ 1 0 0 3,4-methylenedioxyphenyl 167 3-CH₃-4-Cl—C₆H₃ 10 0 5-phenyl-oxazol-4-yl 168 3-CH₃-4-Cl—C₆H₃ 1 0 0 Quinoxalin-2-yl 1693-CH₃-4-Cl—C₆H₃ 1 0 0 1H-Pyrazol-4-yl 170 3-CH₃-4-Cl—C₆H₃ 1 0 01-CH₃-indol-3-yl 171 3-CH₃-4-Cl—C₆H₃ 1 0 0

172 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-iso-propyl-benztriazol-5-yl 1733-CH₃-4-Cl—C₆H₃ 1 0 0 3-n-propoxy-pyridin-2-yl 174 3-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃-5-F—C₆H₃ 175 3-CH₃-4-Cl—C₆H₃ 1 0 1 (2-S(O)₂NHCH₃—C₆H₄)S 1763-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃5-CF₃-isoxazol-4-yl 177 3-CH₃-4-Cl—C₆H₃ 1 0 12-(2,4-F₂—C₆H₃)thiazol-4-yl 178 3-CH₃-4-Cl—C₆H₃ 1 0 02-(CH₃O(CH₂)₂O)-5-NH₂—C₆H₃ 179 3-CH₃-4-Cl—C₆H₃ 1 0 02-phenyl-thiazol-4-yl 180 3-CH₃-4-Cl—C₆H₃ 1 0 0

181 3-CH₃-4-Cl—C₆H₃ 1 0 0

182 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CF₃-C₆H₃ 183 3-CH₃-4-Cl—C₆H₃ 1 0 0

184 3-CH₃-4-Cl—C₆H₃ 1 0 0

185 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-iso-propoxy-C₆H₄ 186 3-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃-benzimidazol-5-yl 187 3-CH₃-4-Cl—C₆H₃ 1 0 1

188 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 189 3-CH₃-4-Cl—C₆H₃ 1 0 0

190 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-tert-butyl-3-CH₃-pyrazol-5-yl 1913-CH₃-4-Cl—C₆H₃ 1 0 0

192 3-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃O-5-F—C₆H₃ 193 3-CH₃-4-Cl—C₆H₃ 1 0 03-NH₂-4-CH₃O—C₆H₃ 194 3-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 1952-CH₃-4-Cl—C₆H₃ 1 0 0 2-CN—C₆H₄ 196 2-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃O-4-F—C₆H₃ 197 3-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-pyrrol-2-yl 1982-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂CH₃-4-NH₂—C₆H₃ 199 2-CH₃-4-Cl—C₆H₃ 1 0 01H-5-F-indol-2-yl 200 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-CH₃O-indol-3-yl 2012-CH₃-4-Cl—C₆H₃ 1 0 0 3-F-4-CH₃—C₆H₃ 202 2-CH₃-4-Cl—C₆H₃ 1 0 01-phenyl-5-CH₃-pyrazol-4-yl 203 2-CH₃-4-Cl—C₆H₃ 1 0 02-(2-phenyl-thiazol-4-yl)-phenyl 204 3-CH₃-4-Cl—C₆H₃ 1 0 01H-5-F-indol-2-yl 205 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CF₃O-4-NH₂—C₆H₃ 2063-CH₃-4-Cl—C₆H₃ 1 0 0 3-iso-propoxy-4-CH₃O—C₆H₃ 207 2-CH₃-4-Cl—C₆H₃ 1 00 1H-5-CH₃O-indol-2-yl 208 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indol-4-yl 2092-CH₃-4-Cl—C₆H₃ 1 0 0 4-CF₃-pyridin-3-yl 210 2-CH₃-4-Cl—C₆H₃ 1 0 0

211 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 212 2-CH₃-4-Cl—C₆H₃ 1 0 03-iso-propoxy-4-CH₃O—C₆H₃ 213 3-CH₃-4-Cl—C₆H₃ 1 0 1 1H-indol-3-yl 2142-CH₃-4-Cl—C₆H₃ 1 0 0

215 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 216 3-CH₃-4-Cl—C₆H₃ 1 0 03-S(O)₂NH₂-4-Cl—C₆H₃ 217 3-CH₃-4-Cl—C₆H₃ 1 0 0

218 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-(pyrrol-1-yl)-3-CN-thien-2-yl 2192-CH₃-4-Cl—C₆H₃ 1 0 0 4-(pyrrol-1-yl)phenyl 220 3-CH₃-4-Cl—C₆H₃ 1 0 01H-indazol-3-yl 221 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃O-NH₂—C₆H₃ 2222-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 223 3-CH₃-4-Cl—C₆H₃ 1 0 0

224 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-S(O)₂CH₃—C₆H₄ 225 3-CH₃-4-Cl—C₆H₃ 1 0 02-(1-CH₃-5-CF₃-pyrazol-3-yl)-thien-5-yl 226 2-CH₃-4-Cl—C₆H₃ 1 0 02-CH₃-5-F—C₆H₃ 227 2-CH₃-4-Cl—C₆H₃ 1 0 0 4-CH₂S(O)₂CH₃—C₆H₄ 2282-CH₃-4-Cl—C₆H₃ 1 0 0 Quinoxalin-2-yl 229 2-CH₃-4-Cl—C₆H₃ 1 0 01H-5-Cl-indol-2-yl 230 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₂S(O)₂CH₃—C₆H₄ 2312-CH₃-4-Cl—C₆H₃ 1 0 1 2-(2,4-F₂—C₆H₃)thiazol-4-yl 232 2-CH₃-4-Cl—C₆H₃ 10 0 3-S(O)₂NH₂—C₆H₄ 233 2-CH₃-4-Cl—C₆H₃ 1 0 1 1H-indol-3-yl 2343-CH₃-4-Cl—C₆H₃ 1 0 0 4-S(O)₂CH₃—C₆H₄ 235 3-CH₃-4-Cl—C₆H₃ 1 0 01-CH₃-indol-2-yl 236 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃-5-CF₃-isoxazol-4-yl 2373-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-2-yl 238 4-S(O)₂CH₃—C₆H₄ 1 0 03,4-Cl₂—C₆H₃ 239 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-indol-3-yl 2403-CH₃-4-Cl—C₆H₃ 1 0 0 [1,8]-naphthyridin-2-yl 241 2-CH₃-4-Cl—C₆H₃ 1 0 03-S(O)₂CH₃—C₆H₄ 242 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-OH—C₆H₄ 243 3-CH₃-4-Cl—C₆H₃1 0 0 3H-Benzthiazol-2-one-6-yl 244 2-CH₃-4-Cl—C₆H₃ 1 0 03-n-propoxy-pyridin-2-yl 245 2-CH₃-4-Cl—C₆H₃ 1 0 03H-Benzthiazol-2-one-6-yl 246 2-CH₃-4-Cl—C₆H₃ 1 0 0 Isoxazol-5-yl 2472-CH₃-4-Cl—C₆H₃ 1 0 0 2,5-(CH₃O)₂—C₆H₃ 248 2-CH₃-4-Cl—C₆H₃ 1 0 01H-pyrazol-4-yl 249 3-CH₃-4-Cl—C₆H₃ 1 0 0 Benzothiazol-6-yl 2502-CH₃-4-Cl—C₆H₃ 1 0 0 3,5-(CH₃)₂-isoxazol-4-yl 251 3-CH₃-4-Cl—C₆H₃ 1 0 04-CF₃-pyridin-3-yl 252 3-CH₃-4-Cl—C₆H₃ 1 0 0 1H-indol-4-yl 2533-CH₃-4-Cl—C₆H₃ 1 0 0 1,5-(CH₃)₂-pyrazol-3-yl 254 2-CH₃-4-Cl—C₆H₃ 1 0 01H-indazol-3-yl 255 3-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂—C₆H₄ 2562-CH₃-4-Cl—C₆H₃ 1 0 1 4-S(O)₂CH₃—C₆H₄ 257 2-CH₃-4-Cl—C₆H₃ 1 0 0Benzthiazol-6-yl 258 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-OH-indol-2-yl 2592-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₂S(O)₂CH₃—C₆H₄ 260 2-CH₃-4-Cl—C₆H₃ 1 0 03,4-methylenedioxyphenyl 261 2-CH₃-4-Cl—C₆H₃ 1 0 0 1-CH₃-pyrrol-2-yl 2622-CH₃-4-Cl—C₆H₃ 1 0 0 3-CH₃-4-NH₂—C₆H₃ 263 3-CH₃-4-Cl—C₆H₃ 1 0 0Isoxazol-5-yl 264 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-OH—C₆H₄ 265 2-CH₃-4-Cl—C₆H₃ 10 0 1H-5-OH-indol-3-yl 266 3-CH₃-4-Cl—C₆H₃ 1 0 0

267 2-CH₃-4-Cl—C₆H₃ 1 0 0

268 2-CH₃-4-Cl—C₆H₃ 1 0 0

269 3-CH₃-4-Cl—C₆H₃ 1 0 0

270 3-CH₃-4-Cl—C₆H₃ 1 0 0

271 2-CH₃O-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 272 2,6-(CH₃)₂-4-Cl—C₆H₂ 1 00 3-CH₃S(O)₂—C₆H₄ 273 2,3-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 2742,5-Cl₂—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 275 2-Cl-4-CH₃—C₆H₃ 1 0 03-CH₃S(O)₂—C₆H₄ 276 2-Cl-5-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 2772-CH₃-4-C(O)CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 278 2-(morpholin-4-yl)- 1 0 03-CH₃S(O)₂—C₆H₄ C₆H₄ 279 3-CH₃CH₂-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 280Naphth-7-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 281 2-tert-butyl-C₆H₄ 1 0 03-CH₃S(O)₂—C₆H₄ 282 Indan-5-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 2832-cyclohexyl-4-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 284 2-C(O)NH₂-4-Cl—C₆H₃ 1 00 3-CH₃S(O)₂—C₆H₄ 285 2-isoxazol-5-yl- 1 0 0 3-CH₃S(O)₂—C₆H₄ 4-Cl—C₆H₃286 2-CH₃-5-Cl—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 287 phenyl 1 0 03-CH₃S(O)₂—C₆H₄ 288 2,4-Cl₂-6-CH₃—C₆H₂ 1 0 0 3-CH₃S(O)₂—C₆H₄ 2893-Cl-4-CH₃—C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 290 2-CN-4-CH₃—C₆H₃ 1 0 03-CH₃S(O)₂—C₆H₄ 291 2-CN-4-CF₃-C₆H₃ 1 0 0 3-CH₃S(O)₂—C₆H₄ 2922-CH₃-pyridin-6-yl 1 0 0 3-CH₃S(O)₂—C₆H₄ 293 Pyrimidin-2-yl 1 0 03-CH₃S(O)₂—C₆H₄ 294 2-Cl-4-F—C₆H₃ 1 0 0 2-Cl-4-CH₃S(O)₂—C₆H₃ 2952-CH₃-4-Cl—C₆H₃ 1 0 0 2-CH₃S(O)₂—C₆H₄ 296 2-CH₃-4-Cl—C₆H₃ 1 0 02-Cl-4-CH₃S(O)₂—C₆H₃ 297 2-CH₃-4-Cl—C₆H₃ 1 0 0 3-S(O)₂NH₂-4-Cl—C₆H₃ 2982-CH₃-4-Cl—C₆H₃ 1 0 0

299 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 3-S(O)₂CH₃—C₆H₄ 300 2-ethyl-4-F—C₆H₃ 1 0 03-S(O)₂CH₃—C₆H₄ 301 2-CH₃-4-Cl—C₆H₃ 1 0 0 1H-5-S(O)₂CH₃-indol-2-yl 3022-CH₃-4-Cl—C₆H₃ 1 0 1

303 3-CH₃-4-Cl—C₆H₃ 1 0 1

304 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0

305 2,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 2-(pyrazol-1-yl)-pyridin-5-yl 3062,4-Cl₂-3-CH₃—C₆H₂ 1 0 0 2-S(O)₂CH₃-thien-5-yl 307 2,4-Cl₂-3-CH₃—C₆H₂ 10 0 4-S(O)₂CH₃—C₆H₄ 308 5-CF₃-pyridin-2-yl 1 0 0 3-S(O)₂CH₃—C₆H₄ 3093,4-Cl₂—C₆H₃ 1 1 0 phenyl 310 3,4-Cl₂—C₆H₃ 1 1 0 4-OCH₃—C₆H₄ 3113,4-Cl₂—C₆H₃ 1 1 0 4-F—C₆H₄ 312 3,4-Cl₂—C₆H₃ 1 1 0 3-SCH₃—C₆H₄ 3133,4-Cl₂—C₆H₃ 1 1 1 phenyl 314 3,4-Cl₂—C₆H₃ 1 1 1 4-OCH₃—C₆H₄ 3153,4-Cl₂—C₆H₃ 1 1 1 4-F—C₆H₄

Examples of compounds of formula (Ig) are listed in Table V below.

TABLE V R¹ X R³ 1 3,4-Cl₂—C₆H₃ CH₂ 3-S(O)₂CH₃—C₆H₄ 2 3,4-Cl₂—C₆H₃ NH3-S(O)₂CH₃—C₆H₄ 3 3,4-Cl₂—C₆H₃ C(O) 3-S(O)₂CH₃—C₆H₄ 4 3,4-Cl₂—C₆H₃ S(O)₂4-S(O)₂CH₃—C₆H₄ 5 3,4-Cl₂—C₆H₃ S(O)₂ C₆H₅

The compounds of formula (I):

wherein:

-   q, s and t are, independently, 0 or 1;-   n and r are, independently, 0, 1, 2, 3, 4 or 5;-   m and p are, independently, 0, 1 or 2;-   X is CH₂, C(O), 0, S, S(O), S(O)₂ or NR³⁷;-   Y is NHR² or OH;-   T is C(O), C(S), S(O)₂ or CH₂;-   R¹ is hydrogen, C₁₋₆ alkyl, aryl or heterocyclyl;-   R² and R⁴⁷ are, independently, hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkyl    or CO(C₁₋₆ alkyl);-   R³ is C₁₋₆ alkyl {optionally substituted by halogen, CO₂R⁴ or    phthalimide}, CR^(3a)R^(3b)R^(3c), C₂₋₄ alkenyl {optionally    substituted by aryl or heterocyclyl}, C₃₋₇ cycloalkyl {optionally    substituted by C₁₋₄ alkyl, aryl or oxo}, C₃₋₇ cycloalkenyl    {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, aryl,    heterocyclyl, thioaryl or thioheterocyclyl;-   R^(3a) is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₇ cycloalkyl;    R^(3b) is aryl, heterocyclyl, S(O)₂aryl or S(O)₂heterocyclyl; and    R^(3c) is C₁₋₆ alkyl, C₁₋₄ haloalkyl, hydroxy, heterocyclyl(C₁₋₄    alkyl) or aryl;    wherein, unless stated otherwise, the foregoing aryl and    heterocyclyl moieties are optionally substituted by: halogen, OH,    SH, NO₂, oxo, C₁₋₆ alkyl {itself optionally substituted by halogen,    OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally substituted by    halogen (such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl,    S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally substituted    by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself optionally    substituted by C₁₋₄ alkyl or oxo) or NR⁴¹C(O)OCH₂(fluoren-9-yl)},    NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy {itself optionally    substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆ alkyl), CO₂R⁴, NR⁵R⁶    or phenyl (itself optionally substituted by halogen or NO₂)}, C₁₋₆    alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀ cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰,    CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴, S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³,    NR⁴⁴S(O)₂R⁴⁵, phenyl {itself optionally substituted by halogen, C₁₋₆    alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy (itself optionally    substituted by halogen, OH or pyridinyl), phenyl (itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl (itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy or C₁₋₆ haloalkoxy)}, heterocyclyl {itself optionally    substituted by halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy, C₁₋₆ haloalkoxy, phenyl (itself optionally substituted by    halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆    haloalkoxy) or heterocyclyl (itself optionally substituted by    halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆    haloalkoxy)}, phenoxy {itself optionally substituted by halogen,    C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,    phenyl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy)}, SCN, CN, SO₃H    (or an alkali metal salt thereof), methylenedioxy or    difluoromethylenedioxy; when aryl is phenyl adjacent substituents    may join to form, together with the phenyl ring to which they are    attached, a dihydrophenanthrene moiety;-   d is 0, 1 or 2;-   R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹,    R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆ alkyl, aryl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy);-   R¹⁵, R³⁸, R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁ cycloalkyl), C₃₋₆ alkenyl,    aryl (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy) or heterocyclyl    (itself optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy);    or an N-oxide thereof; or a pharmaceutically acceptable salt    thereof; or a solvate thereof; have activity as pharmaceuticals, in    particular as modulators of chemokine receptor (especially CCR3)    activity, and may be used in the treatment of autoimmune,    inflammatory, proliferative or hyperproliferative diseases, or    immunologically-mediated diseases (including rejection of    transplanted organs or tissues and Acquired Immunodeficiency    Syndrome (AIDS)).

In one aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, Sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle.

In another aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle.

In a further aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung or idiopathic interstitial pneumonia;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Lupus disorders (such as lupus    erythematosus or systemic lupus), erythematosus, Hashimoto's    thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome,    eosinophilia fascitis, hyper IgE syndrome, leprosy (such as    lepromatous leprosy), Peridontal disease, sezary syndrome,    idiopathic thrombocytopenia pupura or disorders of the menstrual    cycle.

The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″),(Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceuticallyacceptable salt thereof or a solvate thereof, are also H1 antagonistsand may be used in the treatment of allergic disorders.

The compounds of formula (I) (as defined anywhere herein), (I′), (Ia″),(Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceuticallyacceptable salt thereof or a solvate thereof, may also be used tocontrol a sign and/or symptom of what is commonly referred to as a cold(for example a sign and/or symptom of a common cold or influenza orother associated respiratory virus infection).

Thus, in a further aspect the present invention provides a compound offormula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′),(Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptablesalt thereof or a solvate thereof, which is both a modulator ofchemokine receptor (especially CCR3) activity and an H1 antagonist.

According to a further feature of the invention there is provided acompound of the formula (I) (as defined anywhere herein), (I′), (Ia″),(Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceuticallyacceptable salt thereof or a solvate thereof, for use in a method oftreatment of a warm blooded animal (such as man) by therapy (includingprophylaxis).

According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR3 receptor activity) in a warm blooded animal, such as man, in needof such treatment, which comprises administering to said animal aneffective amount of a compound of the formula (I) (as defined anywhereherein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig)or a pharmaceutically acceptable salt thereof or a solvate thereof.

According to another feature of the present invention there is provideda method for antagonising H1 in a warm blooded animal, such as man, inneed of such treatment, which comprises administering to said animal aneffective amount of a compound of the formula (I) (as defined anywhereherein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig),or a pharmaceutically acceptable salt thereof or a solvate thereof.

The invention also provides a compound of the formula (I) (as definedanywhere herein), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If)or (Ig), or a pharmaceutically acceptable salt thereof or a solvatethereof, for use as a medicament.

In another aspect the invention provides the use of a compound offormula (I) (as defined anywhere herein), (I′), (Ia″), (Ia), (Ia′),(Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptablesalt thereof or a solvate thereof, in the manufacture of a medicamentfor use in therapy (for example modulating chemokine receptor activity(especially CCR3 receptor activity) or antagonising H1 in a warm bloodedanimal, such as man, or both).

In a further aspect the present invention provides the use of a compoundof the formula (I), wherein: q, s and t are, independently, 0 or 1; nand r are, independently, 0, 1, 2, 3, 4 or 5; m and p are,independently, 0, 1 or 2; X is CH₂, C(O), O, S, S(O), S(O)₂ or NR³⁷; Yis NHR² or OH; T is C(O), C(S), S(O)₂ or CH₂; R¹ is hydrogen, C₁₋₆alkyl, aryl or heterocyclyl; R² and R⁴⁷ are, independently, hydrogen,C₁₋₆ alkyl, aryl(C₁₋₄)alkyl or CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl{optionally substituted by halogen, CO₂R⁴ or phthalimide}, C₃₋₇cycloalkyl {optionally substituted by C₁₋₄ alkyl or oxo}, C₃₋₇cycloalkenyl {optionally substituted by oxo, C₁₋₆ alkyl or aryl}, arylor heterocyclyl; wherein, unless stated otherwise, the foregoing aryland heterocyclyl moieties are optionally substituted by:

-   halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted    by halogen, OC(O)C₁₋₆ alkyl, S(O)₂R⁴⁸, phenyl (itself optionally    substituted by halo (such as one or two chlorine or fluorine atoms),    C₁₋₆ alkyl, S(O)₂R³⁸ or C(O)NR³⁹R⁴⁰), naphthyloxy (itself optionally    substituted by halo or C₂₋₆ alkenyl), C₃₋₁₀ cycloalkyl (itself    optionally substituted by C₁₋₄ alkyl or oxo) or    NR⁴¹C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆ alkoxy    (itself optionally substituted by halogen, C₁₋₆ alkoxy, NHCO₂(C₁₋₆    alkyl), CO₂R⁴, NR⁵R⁶ or phenyl (itself optionally substituted by    halogen or NO₂)), C₁₋₆ alkylthio, C₁₋₆ haloalkylthio, C₃₋₁₀    cycloalkyl, NR⁷R⁸, NR⁹C(O)R¹⁰, CO₂R¹¹, C(O)NR¹²R¹³, C(O)R¹⁴,    S(O)_(d)R¹⁵, S(O)₂NR⁴²R⁴³, NR⁴⁴S(O)₂R⁴⁵, phenyl (itself optionally    substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆    alkoxy (itself optionally substituted by halo, OH or pyridinyl)),    heterocyclyl (itself optionally substituted by halo, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy    (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,    CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), SCN, CN, SO₃H (or an    alkali metal salt thereof) or methylenedioxy; when aryl is phenyl    adjacent substituents may join to form, together with the phenyl    ring to which they are attached, a dihydrophenanthrene moiety; d is    0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R³⁷,    R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are, independently, hydrogen, C₁₋₆    alkyl or aryl (itself optionally substituted by halo, C₁₋₆ alkyl,    C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); R¹⁵, R³⁸,    R⁴⁵ and R⁴⁸ are, independently, C₁₋₆ alkyl (optionally substituted    by halogen, hydroxy or C₃₋₁₀ cycloalkyl) or aryl (itself optionally    substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆    alkoxy or C₁₋₆ haloalkoxy); or a pharmaceutically acceptable salt    thereof; or a solvate thereof; in the manufacture of a medicament    for use in therapy (for example modulating chemokine receptor    activity (especially CCR3 receptor activity) or antagonising H1 in a    warm blooded animal, such as man, or both).

In another aspect the present invention provides the use of a compoundof the formula (I′):

wherein: q is 0 or 1; n and r are, independently, 0, 1, 2, 3, 4 or 5; mand p are, independently, 0, 1 or 2; X is CH₂, CO, O, S, S(O), S(O)₂ orNR³⁷; Y is NHR² or OH; T is CO, CS, SO₂ or CH₂; R¹ is hydrogen, C₁₋₆alkyl, aryl or heterocyclyl; R² is hydrogen, C₁₋₆ alkyl, aryl(C₁₋₄)alkylor CO(C₁₋₆ alkyl); R³ is C₁₋₆ alkyl {optionally substituted by halogen,CO₂R⁴ or phthalimide}, C₃₋₇ cycloalkyl {optionally substituted by C₁₋₄alkyl or oxo}, C₃₋₇ cycloalkenyl {optionally substituted by C₁₋₆ alkylor aryl}, aryl or heterocyclyl; wherein, unless stated otherwise, theforegoing aryl and heterocyclyl moieties are optionally substituted by:halogen, OH, SH, NO₂, oxo, C₁₋₆ alkyl (itself optionally substituted byhalogen, OC(O)C₁₋₆ alkyl, phenyl (itself optionally substituted by halo(such as one or two chlorine or fluorine atoms), C₁₋₆ alkyl, SO₂R³⁸ orCONR³⁹R⁴⁰), naphthyloxy (itself optionally substituted by halo or C₂₋₆alkenyl) or NR⁴C(O)OCH₂(fluoren-9-yl)), NR⁴¹C(O)OCH₂(fluoren-9-yl), C₁₋₆alkoxy (itself optionally substituted by halogen, CO₂R⁴, NR⁵R⁶ or phenyl(itself optionally substituted by halogen or NO₂)), C₁₋₆ alkylthio,nitro, C₃₋₇ cycloalkyl, NR⁷R⁸, NR⁹COR¹⁰, CO₂R¹¹, CONR¹²R¹³, COR¹⁴,SO_(d)R¹⁵, SO₂NR⁴²R⁴³, NR⁴⁴SO₂R⁴⁵, phenyl (itself optionally substitutedby halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂ or C₁₋₆ alkoxy (itselfoptionally substituted by halo, OH or pyridinyl)), heterocyclyl (itselfoptionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,C₁₋₆ alkoxy or C₁₋₆ haloalkoxy), phenoxy (itself optionally substitutedby halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy or C₁₋₆haloalkoxy), SCN, CN, SO₃H (or an alkali metal salt thereof) ormethylenedioxy; when aryl is phenyl adjacent substituents may join toform, together with the phenyl ring to which they are attached, adihydrophenanthrene moiety; d is 0, 1 or 2; R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R³⁷, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are,independently, hydrogen, C₁₋₆ alkyl or aryl (itself optionallysubstituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂, C₁₋₆ alkoxy orC₁₋₆ haloalkoxy); R¹⁵, R³⁸ and R⁴⁵ are, independently, C₁₋₆ alkyl oraryl (itself optionally substituted by halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, C₁₋₆ alkoxy or C₁₋₆ haloalkoxy); or a pharmaceuticallyacceptable salt thereof; or a solvate thereof; in the manufacture of amedicament for use in therapy (for example modulating chemokine receptoractivity (especially CCR3 receptor activity) in a warm blooded animal,such as man).

The invention further provides the use of a compound of formula (I) (asdefined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id),(Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for use in the treatment of:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle;    in a warm blooded animal, such as man.

In a further aspect a compound of formula (I) (as defined anywhereabove), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig),or a pharmaceutically acceptable salt thereof, is useful in thetreatment of asthma {such as bronchial, allergic, intrinsic, extrinsicor dust asthma, particularly chronic or inveterate asthma (for examplelate asthma or airways hyper-responsiveness)}; or rhinitis {includingacute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (I) (as defined anywhereabove), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig),or a pharmaceutically acceptable salt thereof, is useful in thetreatment of asthma.

The invention also provides the use of a compound of formula (I) (asdefined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id),(Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for use in the treatment of a signand/or symptom of what is commonly referred to as a cold (for example asign and/or symptom of common cold or influenza or other associatedrespiratory virus infection).

The present invention also provides a the use of a compound of formula(I) (as defined anywhere above), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic),(Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for use in the treatment of asthma orrhinitis.

The present invention further provides a method of treating a chemokinemediated disease state (especially a CCR3 mediated disease state,especially asthma) or an H1 mediated disease state (such as an allergicdisorder) in a warm blooded animal, such as man, which comprisesadministering to a mammal in need of such treatment an effective amountof a compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic),(Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt thereofor solvate thereof.

The present invention also provides a method of treating a sign and/orsymptom of a cold (for example a sign and/or symptom of common cold orinfluenza or other associated respiratory virus infection) in a warmblooded animal, such as man, which comprises administering to a mammalin need of such treatment an effective amount of a compound of formula(I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), ora pharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a warm blooded animal, such as man, in particularmodulating chemokine receptor (for example CCR3 receptor) activity orantagonising H1, said ingredient is normally formulated in accordancewith standard pharmaceutical practice as a pharmaceutical composition.

The present invention further provides a method of treating a chemokinemediated disease state (especially a CCR3 mediated disease state,especially asthma) in a warm blooded animal, such as man, whichcomprises administering to a mammal in need of such treatment aneffective amount of a compound of formula (I), (I′), (Ia″), (Ia), (Ia′),(Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptablesalt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a warm blooded animal, such as man, in particularmodulating chemokine receptor (for example CCR3 receptor) activity, saidingredient is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), (I′), (Ia″), (Ia), (Ia′), (Ib), (Ic), (Id), (Ie), (If) or (Ig), ora pharmaceutically acceptable salt thereof or a solvate thereof (activeingredient), and a pharmaceutically acceptable adjuvant, diluent orcarrier. In a further aspect the present invention provides a processfor the preparation of said composition which comprises mixing activeingredient with a pharmaceutically acceptable adjuvant, diluent orcarrier. Depending on the mode of administration, the pharmaceuticalcomposition will preferably comprise from 0.05 to 99% w (percent byweight), more preferably from 0.05 to 80% w, still more preferably from0.10 to 70% w, and even more preferably from 0.10 to 50% w, of activeingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the lung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, aerosols, dry powder formulations,tablets, capsules, syrups, powders, granules, aqueous or oily solutionsor suspensions, (lipid) emulsions, dispersible powders, suppositories,ointments, creams, drops and sterile injectable aqueous or oilysolutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound,preferably in the range of 0.1 mgkg⁻1 to 20 mgkg⁻1 of this invention,the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), (I′), (Ia″), (Ia), (Ia′), (Ib),(Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically-acceptable saltthereof (hereafter Compound X), for therapeutic or prophylactic use inhumans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur. 179 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0

(c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate1.0

(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389 Croscarmellosesodium 100 Magnesium stearate 1.0

(e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solutionto 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

-   (i) when given, 1H NMR data is quoted and is in the form of delta    values for major diagnostic protons, given in parts per million    (ppm) relative to tetramethylsilane (TMS) as an internal standard,    determined at 300 MHz or 400 MHz using perdeuterio DMSO-D6    (CD₃SOCD₃) or CDCl₃ as the solvent unless otherwise stated;-   (ii) mass spectra (MS) were run with an electron energy of 70    electron volts in the chemical ionisation (CI) mode using a direct    exposure probe; where indicated ionisation was effected by electron    impact (EI) or fast atom bombardment (FAB); where values for m/z are    given, generally only ions which indicate the parent mass are    reported, and unless otherwise stated the mass ion quoted is the    positive mass ion—(M+H)⁺;-   (iii) the title and sub-titled compounds of the examples and methods    were named using the AUTONOM program from Beilstein    informationssysteme GmbH;-   (iv) unless stated otherwise, reverse phase HPLC was conducted using    a Symmetry, NovaPak or Ex-Terra reverse phase silica column; and-   (v) the following abbreviations are used:

RPHPLC reverse phase HPLC RT room temperature DEADdiethyl-azodicarboxylate NMP N-methylpyrrolidone CDI N,N′-carbonyldiimidazole MTBE tert-butyl methyl ether DMF N,N-dimethylformamide Bocor BOC tert-butoxycarbonyl HPLC high pressure liquid chromatographyPYBROP ™ bromo-tris-pyrrolidino-phosphonium hexafluorophosphate THFtetrahydrofuran DCM dichloromethane TFA trifluoroacetic acid m.pt.melting point DMSO dimethylsulfoxide Ac Acetate aq aqueous IPAiso-propyl alcohol equiv. equivalents

EXAMPLE 1

This Example illustrates the preparation of4-(3,4-dichlorophenoxy)piperidine.

Step a: tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate

Diethyl azodicarboxylate (41.0 ml) was added to a solution oftriphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) intetrahydrofuran (400 ml) was added dropwise over 30 min. The solutionwas stirred at room temperature for 16 hours and concentrated to a smallvolume. Purification by chromatography (ethyl acetate: iso-hexane 95:5)gave the sub-title compound as an oil (61.3 g).

MS: APCI(+ve): 246 (M-BOC+2H)

Step b: 4-(3,4-Dichlorophenoxy)piperidine

The product from Step a was dissolved in dichloromethane (600 ml) andtrifluoroacetic acid (300 ml) was added. After 24 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the sub-titled product as a solid (36.6 g). The freebase was liberated by addition of aqueous NaOH (2M) and extraction withethyl acetate followed by evaporation of solvent to give the titlecompound as a gum (25 g).

¹H NMR: δ(CDCl₃) 1.77 (1H, br s), 2.05-2.26 (4H, m), 3.20-3.49 (4H, m),4.61 (1H, s), 6.69-7.52 (3H, m).

EXAMPLE 2

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanoneacetate (acetate salt of Compound 281 in Table I).

Step a: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g)followed by NaBH(OAc)₃ (1.81 g) and acetic acid (0.37 g). After 18 hoursat room temperature aqueous NaOH (1M) solution and diethyl ether wereadded. The product was extracted with diethyl ether, the combinedorganic extracts dried with MgSO₄ and concentrated. Purification bysilica chromatography (dichloromethane:methanol 92:8) gave the sub-titleproduct (1.97 g).

MS: APCl(+ve): 429 (M+H)

Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine

The product of Step a was dissolved in dichloromethane (30 ml) andtrifluoroacetic acid (15 ml) was added. After 4 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the trifluoroacetate salt of the sub-titled productas a solid (1.15 g). The free base was liberated by addition of aqueousNaOH (2M) and extraction with ethyl acetate followed by evaporation ofsolvent to give the sub-title compound as a solid (0.68 g).

¹H NMR: δ(CDCl₃) 1.38-1.51 (2H, m), 1.74-2.02 (6H, m), 2.38-2.50 (3H,m), 2.56-2.61 (2H, m), 2.79-2.86 (2H, m), 3.14-3.18 (2H ,m), 4.22-4.28(1H, m), 6.73-7.32(3H, m).

Step c:[4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanoacetate

The product of Step b (0.15 g) was dissolved in THF (4 ml),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.235g), 3-methylsulphonylbenzoic acid (0.091 g) andN,N-di-iso-propylethylamine (0.238 ml) were added. After 18 hours atroom temperature ethyl acetate and aqueous NaHCO₃ solution were added.The product was extracted with ethyl acetate, the combined organicextracts dried with Na₂SO₄ and concentrated. Purification by reversephase HPLC (with a gradient eluent system (45% MeCN/NH₄OAc_(aq) (0.1%)to 95% MeCN//NH₄OAc_(aq) (0.1%)) gave the title compound (0.095 g).

¹H NMR: δ(DMSO-D6) 1.44-1.94 (8H, m), 2.37-2.77 (5H, m), 3.07-3.55 (6H,m), 4.40 (1H, m), 4.50-4.53 (1H, m), 6.96-8.02 (7H, m).

Melting point: 60-61° C. becomes a gum.

Melting point of free base: 154° C.

EXAMPLE 3

This Example illustrates the preparation of(4-amino-3-methoxy-phenyl)-[4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanoneacetate (Compound 282 of Table I).

The compound was prepared by the method of Example 2, Step c using4-amino-3-methoxybenzoic acid to give the title compound as a solid(0.016 g).

¹H NMR: δ(DMSO-D6) 1.32-2.01 (8H, m), 2.28-2.88 (5H, m), 3.32 (4H, brs), 3.77 (3H, s), 4.13 (2H, br s), 4.39-4.44 (1H, m), 6.59-7.50 (6H, m).

Melting point: 171° C. becomes a gum.

EXAMPLE 4

This Example illustrates the preparation of(4-amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone(Compound 4 of Table II).

Step a: tert-Butyl 4-(3,4-difluorophenoxy)-1-piperidinecarboxylate

This compound was prepared according to the method of Example 1 Step ausing 3,4-difluorophenol to afford the compound as an oil (5.4 g).

MS: ESI(+ve): 213 (M-BOC+H)

Step b: 4-(3,4-Difluorophenoxy)piperidine

This compound was prepared according to the method of Example 1 Step bto afford the compound as a pale yellow oil (3 g).

MS: ESI(+ve): 214 (+H)

Step c:3-[4-(3,4-Difluoro-phenoxy)piperidin-1-yl]-Pyrrolidine-1-carboxylic acidtert-butyl ester

The product of Step b (0.5 g) was dissolved in 1,2-dichloroethane (7ml). tert-Butyl 3-oxo-1-pyrrolidinecarboxylate (0.43 g) was addedfollowed by NaBH(OAc)₃ (0.7 g) and acetic acid (0.08 g). After 24 hoursat room temperature aqueous NaOH (1M) solution and diethyl ether wereadded. The product was extracted with diethyl ether, the combinedorganic extracts dried with MgSO₄ and concentrated. Purification bysilica chromatography (100% ethyl acetate) gave the sub-title product(0.79 g).

MS: ESI(+ve): 383 (M+H)

Step d: 3,4-Difluorophenyl 1-(3-pyrrolidinyl)-4-piperidinyl ether

The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10ml) was added and the reaction stirred for 3 hrs. Organic solvent wasevaporated and aqueous NaOH (2M) added. The product was extracted withethyl acetate, the combined organic extracts dried with Na₂SO₄ andconcentrated to give the sub-title product as an oil (0.54 g).

¹H NMR: δ(CDCl₃) 1.60-2.39 (9H, m), 2.70-3.13 (6H, m), 4.19-4.22 (1H,m), 6.58-7.52 (3H, m).

Step e:(4-Amino-3-methoxy-phenyl)-{3-[4-(3,4-difluoro-phenoxy)-piperidin-1-yl]-pyrrolidin-1-yl}-methanone

This compound was prepared by the method of Example 2 Step c using4-amino-3-methoxybenzoic acid to give the title compound as a solid(0.151 g).

¹H NMR: δ(CDCl₃) 1.95-2.43 (5H, m), 2.69-2.81 (3H, m), 3.42-3.91 (10H,m), 4.19-4.23 (1H, m), 6.56-7.25 (6H, m).

Melting point: 138-139° C.

EXAMPLE 5

This Example illustrates the preparation of(4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone(Compound 1 in Table II).

Step a: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

This compound was prepared by the method of Example 2, Step a using4-(3,4-difluorophenoxy)piperidine to give the sub-title compound as asolid (0.48 g).

MS: APCl(+ve): 397 (M+H)

Step b: 4-(3,4-Difluoro-phenoxy)-[1,4′]bipiperidinyl

This compound was prepared by the method of Example 2, Step b to givethe sub-title compound as a solid (0.36 g).

MS: APCl(+ve): 297 (M+H)

Step c:(4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone

This compound was prepared by the method of Example 2, Step c using4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.133g).

¹H NMR: δ(CDCl₃) 1.50-1.60 (2H, m), 1.85-1.93 (4H, m), 2.04-2.08 (2H,m), 2.58-2.62 (2H, m), 2.69-2.75 (1H, m), 2.86-2.90 (4H, m), 3.86 (3H,s), 3.86 (2H, m), 4.25-4.30(1H, m), 6.50-6.61 (1H, m), 6.65 (1H, dd),6.70-6.75 (1H. m), 6.85 (1H, dt), 6.94 (1H, s), 7.01-7.09 (1H, m).

EXAMPLE 6

This Example illustrates the preparation of(4-amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-yl]-methanone(Compound 2 in Table II).

Step a: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

This compound was prepared by the method of Example 2, Step a using3-oxo-piperidine-1-carboxylic acid tert-butyl ester to give thesub-title compound as a solid (0.946 g).

MS: APCl(+ve): 397 (M+H)

Step b: 4-(3,4-Difluoro-phenoxy)-[1,3′]bipiperidinyl

This compound was prepared by the method of Example 2, Step b to givethe sub-title compound as a solid (0.706).

MS: ESI(+ve): 297 (M+H)

Step c:(4-Amino-3-methoxy-phenyl)-[4-(3,4-difluoro-phenoxy)-[1,3′]bipiperidinyl-1-yl]-methanone

This compound was prepared by the same method as Example 2, Step c using4-amino-3-methoxybenzoic acid to give the title compound as a gum (0.070g).

¹H NMR: δ(CDCl₃) 1.41-1.67 (4H, m), 1.73-1.80 (2H, m), 1.86-2.00 (2H,m), 2.44 (3H, m), 3.00-3.13 (2H, m), 2.79-2.91 (2H, m), 3.82 (3H, s),3.97-4.01 (1H, d), 4.14-4.17 (1H, d), 4.32 (1H, sept), 4.89 (2H, s),6.67 (1H, d), 6.75-6.79 (1H, m), 6.80 (1H, dd), 6.87 (1H, s), 6.98-7.06(1H, m), 7.27 (1H, q).

EXAMPLE 7

This Example illustrates the preparation of4-(3,4-dichloro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl(Compound 280 in Table I).

The product of Example 2, Step b (0.2 g) was dissolved in acetone (4ml). Potassium carbonate [0.134 g dissolved in H₂O (1.2 ml)] was thenadded, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.168g) and the reaction left to stir for 1 hr. Water was then added and theproduct extracted with ethyl acetate. The combined organic extractsdried with Na₂SO₄ and concentrated. Purification reverse phase HPLC(with a gradient eluent system (25% MeCN/NH₄OAc_(aq) (0.1%) to 95%MeCN//NH₄OAc_(aq) (0.1%)) gave the title compound as a solid (0.077 g).

¹H NMR: δ(DMSO-D6) 1.45-1.58 (4H, m), 1.79-1.90 (4H, m), 2.28-2.46 (5H,m), 2.66-2.73 (2H, m), 3.67-3.71 (2H, m), 4.35-4.43 (1H, m), 6.93-8.60(9H, m).

Melting point: 139-140° C.

EXAMPLE 8

This Example illustrates the preparation of4-(3,4-difluoro-phenoxy)-1′-(5-pyridin-2-yl-thiophene-2-sulfonyl)-[1,4′]bipiperidinyl(Compound 3 in Table II).

This compound was prepared by the method of Example 7 using product ofExample 5, step b to give the title compound as a solid (0.095 g).

¹H NMR: δ(CDCl₃) 1.67-1.80 (4H, m), 1.87-2.01 (1H, t), 2.30 (1H, t),2.39-2.50 (2H, m), 2.74-2.78 (2H, m), 3.89 (2H, d), 4.16-4.20 (1H, m),6.56-6.60 (1H, m), 6.67-6.63 (1H, m), 7.03 (1H, q), 7.26 (1H, t), 7.52(1H, d), 7.53 (1H, d), 7.70 (1H, d), 7.76 (1H, dt), 8.60 (1H, d).

Melting point: 128-129° C.

EXAMPLE 9

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone(Compound 293 Table I).

Step 1: Preparation of 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) intetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g,0.77 mol). The resultant slurry was stirred for 30 minutes beforecooling the reaction mixture with ice/water, acetic acid (47 ml) is thenadded (exotherm) which caused precipitation. The slurry was allowed towarm to room temperature before the addition of sodiumtriacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF(500 ml). The resultant slurry was stirred overnight at roomtemperature. To the reaction mixture was added water (2000 ml) to give asolution. The solution was then extracted with diethyl ether (3×1800ml). The aqueous phase was basified with 10% aq NaOH (950 ml) andextracted with dichloromethane (DCM) (3×1500 ml). The combined DCMlayers are dried (MgSO₄), filtered and the solvent removed to give thesub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H)285).

Step 2: Preparation of4-(3,4-dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

To a solution of potassium tert-butoxide (139.0 g, 1.24 mol) in THF (500ml) was added a solution of the product of Step 1 (176.2 g, 0.62 mol) inTHF (1000 ml). The reaction mixture was stirred 10 minutes before theadditon of 3,4 dichlorofluorobenzene (122.8 g, 0.74 mol), this caused agreen colouration that subsequently faded. The reaction mixture was thenheated at reflux for 90 minutes. The reaction mixture was then cooled toroom temperature before the addition of saturated NaHCO₃ (1600 ml). Thelayers were separated and the organic layer stripped to leave an orangesemi-solid. The solid was dissolved in DCM (1500 ml) and dried (MgSO₄),filtered and the solvent removed. To the resultant solid was addedmethyl tert-butyl ether (MTBE) (54 ml) and iso-hexane (1000 ml) to givea slurry which was stirred overnight. The slurry was then filtered andwashed with isohexane (200 ml) and the solid dried in vacuo at 50° C. togive the sub-titled compound as a pale powder, (211.6 g, 80%; MS: (M+H)429).

Step 3: Preparation of 4-(3,4-dichlorophenoxy)-[1,4′]bipiperidine

The product of Step 2 (10.15 g, 23.6 mmol) was dissolved indichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol)added and the resultant solution stirred. After 90 minutes thedichloromethane and trifluoroacetic acid were removed on a rotaryevaporator. The resultant oil was partitioned between ethyl acetate (100ml) and 2M aq NaOH (100 ml). The layers were separated and the organicsextracted with 10% aq citric acid (100 ml). The layers were separatedand the aqueous basified with 2M aq NaOH and extracted with ethylacetate (200 ml). The organics were dried (MgSO₄), filtered and thesolvent removed to give the sub-titled product as a pale oil whichsolidified on standing (4.62 g, 59%; MS: (M+H) 329).

Step 4: Preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-phenyl)-methanone

Oxalyl chloride (55 ml, 0.63 mol) was added dropwise over 10 minutes toa stirred suspension of 2-methanesulfonyl-benzoic acid (7.1 g, 0.036) inDCM (550 ml) containing DMF (0.5 ml). The solution was then stirred for2 hours at room temperature. The solution was then evaporated to give asolid that was redissolved in dichloromethane and again evaporated togive a yellow solid. The solid acid chloride was dissolved in DCM (275ml) and was added over 10 minutes to a stirred solution of the productof Step 3 (11.0 g, 0.033 mol) and triethylamine (15.4 ml, 0.11 mol) indichloromethane (125 ml). The resultant solution was stirred at roomtemperature for 16 hours. The solution was then washed with water (500ml), 1M aq NaOH (500 ml) and water (2×500 ml). The organic phase wasdried (MgSO₄), filtered and the solvent removed to give a pale yellowfoam. The foam was triturated with diethyl ether to give the titlecompound (12.96 g, 76%).

Melting point 141° C.

¹H NMR: (400 MHz, CDCl₃) δ 1.39-1.63 (1H, m), 1.72-2.04 (6H, m),2.42-2.68 (2H, m), 2.73-2.92 (3H, m), 3.00-3.08 (1H, m), 3.23 (1H, s),3.28 (2H, s), 3.34-3.40 (1H, m), 3.46-3.52 (1H, m), 4.21-4.30 (1H, m),4.62-4.68 (1H, m), 4.80-4.86 (1H, m), 6.72-6.76 (1H, m), 6.97-7.00 (1H,m), 7.28-7.32 (1H, m), 7.32-7.37 (1H, m), 7.56-7.61 (1H, m), 7.64-7.70(1H, m), 8.05-8.10 (1H, m).

EXAMPLE 10

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone(Compound 281 Table I).

Oxalyl chloride (30 mls, 0.35 mol) was added dropwise over 10 minutes toa stirred suspension of 3-methanesulfonyl-benzoic acid (6 g, 0.03) inDCM (300 ml) containing DMF (0.3 ml). The solution was then stirred for4 hours at room temperature. The solution was then evaporated under highvacuum to give a solid which was redissolved in dichloromethane andagain evaporated to give a yellow solid. The solid acid chloride wasdissolved in DCM (100 ml) and was added over 10 minutes to a stirredsolution of the product of step 3 of Example 9 (9.3 g, 0.028 mol) andtriethylamine (8.4 ml, 0.06 mol) in dichloromethane (100 ml). Theresultant solution was stirred at room temperature for 3 hours. Thesolution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) andwater (2×100 ml). The organic phase was dried (MgSO₄), filtered and thesolvent removed to give a pale yellow foam. The foam was dissolved inmethanol (100 ml) and allowed to crystallise. The crystals werefiltered, washed with methanol and then dried to give the title compound(12.2 g, 84%).

Melting point 157° C.

¹H NMR: (400 MHz, CDCl₃) δ1.40-1.65 (2H, in), 1.75-1.85 (3H, m),1.93-2.03 (3H, m), 2.42-2.51 (2H, m), 2.58 (1H, tt), 2.74-2.91 (3H, m),3.00-3.14 (1H, m), 3.07 (3H, s), 3.62-3.76 (1H, m), 4.27 (1H, septet),4.69-4.80 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.31 (1H, d), 7.64 (1H,t), 7.69 (1H, dt), 7.97-7.98 (1H, m), 8.00 (1H, dt).

The hydrochloride salt (melting point 159° C.) was prepared byevaporation to dryness of a clear solution of Compound 281 of Table Iand HCl in ethanol.

EXAMPLE 11

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(2-methanesulfonyl-thiophen-5-yl)-methanone(Compound 332 of Table I).

Oxalyl chloride (32 ml, 0.37 mol) was added dropwise over 10 minutes toa stirred suspension of 5-(methylsulfonyl)-2-thiophenecarboxylic acid(6.64 g, 0.032) in DCM (300 ml) containing DMF (0.3 ml). The solutionwas then stirred for 2 hours at room temperature. The solution was thenremoved to give a solid which was redissolved in dichloromethane and thesolvent again removed to give a yellow solid. The solid acid chloridewas dissolved in DCM (150 ml) and was added over 10 minutes to a stirredsolution of the product of step 3 of Example 9 (10 g, 0.03 mol) andtriethylamine (9 ml, 0.065 mol) in dichloromethane (300 ml). Theresultant solution was stirred at room temperature for 2 hours. Thesolution was then washed with water (100 ml), 1M aq NaOH (2×100 ml) andwater (300 ml). The organic phase was dried (MgSO₄), filtered and thesolvent removed to give an orange foam. The solid was dissolved indichloromethane (200 ml) and purified by chromatography using ethylacetate and then acetone as the eluant. The purified material wasprecipitated from acetone by the addition of iso-hexane. The crystalswere filtered, washed with isohexane and then dried to give the titlecompound (11.5 g, 74%).

Melting point: 153-154° C.

¹H NMR (399.98 MHz, DMSO-D6) δ 1.42-1.48 (2H, in), 1.56-1.62 (2H, m),1.77-1.84 (2H, m), 1.90-1.96 (2H, m), 2.37-2.43 (2H, m), 2.56-2.63 (2H,m), 2.75-2.80 (2H, m), 2.89-3.14 (2H, m), 3.29-3.32 (1H, m), 3.41 (3H,s), 4.41-4.45 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.49 (2H, q), 7.77(1H, d).

EXAMPLE 12

This Example illustrates the preparation of[4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone(Compound 1 of Table IV)

A solution of 4-(2-methyl-4-chloro-phenoxy)-piperidine (0.87 mmol) and1-(3-methanesulfonyl-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5 ml)and glacial acetic acid (1 mmol) was stirred at room temperature for 1hour after which sodium triacetoxy borohydride (2 mmol) was added. Theresulting mixture was stirred at RT for 24 hours, evaporated on tosilica (2 g) and placed on to a Mega Bond elut cartridge (10 g Silica).The product was eluted with DCM/MeOH mixtures and further purified byReverse Phase preparative chromatography, MeOH/aqueous TFA gradient on aSymmetry column. The free base was isolated by dissolving in EtOAc andwashing with sodium bicarbonate solution, drying the organic layer withMgSO₄ and evaporation left the product as a white solid (0.047 g; M.pt.83-84° C.).

¹H NMR (300 MHz, DMSO-D6) δ 1.2-2.8 (bm, 14H), 2.15 (s, 3H), 3.1 (bm,1H), 3.25 (s, 3H), 3.5 (bm, 1H), 4.4 (bm, 1H), 4.5(bm, 1H), 7.0 (d, 1H),7.12 (m, 1H), 7.2 (d, 1H), 7.7 (m, 2H), 7.9 (s, 1H), 8.0 (dd, 1H).

EXAMPLE 13

This Example illustrates the preparation of(4-amino-3-methoxy-phenyl)-[4-(4-chloro-2-methyl-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanoneditrifluoroacetate (Compound 23 of Table IV).

A solution of the 4-(4-chloro-2-methyl-phenoxy)-piperidine (0.87 mmol)and 1-(4-nitro-3-methoxy-benzoyl)-piperidin-4-one (0.925 mmol) in NMP (5ml) and glacial acetic acid (1 mmol) was stirred at RT for 1 hour afterwhich sodium triacetoxy borohydride (2 mmol) was added. The resultingmixture was stirred at RT for 24 hours, evaporated on to silica (2 g)and placed on to a Mega Bond elut cartridge (10 g Si). The product waseluted with DCM/MeOH mixtures and further purified by SCX, eluting theproduct with 10% aq NH₃ in MeOH. The nitro compound was dissolved in THF(10 ml) and hydrogenated over 10% Pd on C at 3 atmospheres in Petericapparatus. The mixture was filtered and the filtrate evaporated, theresidue was then purified by RPHPLC, using a Symmetry column and elutingwith MeOH/aqueous TFA mixtures. The product was isolated as thetrifluoroacetate by evaporation of the appropriate HPLC fractions (0.046g; m.pt. 84-85° C.).

¹H NMR (400 MHz, DMSO-D6) δ 1.4-2.4 (m, 13H), 2.9 (m, 2H), 3.15 (m, 2H),3.4 (m, 1H), 3.55 (m, 2H), 3.8 (s, 3H), 4.2 (bs, 2H), 4.55 and 4.8 (2bm,1H), 6.68 (d, 1H), 6.82 (d, 1H), 6.85 (s, 1H), 7.0-7.22 (m, 2H), 7.25(s, 1H), 9.5 (bm, 1H).

EXAMPLE 14

This Example illustrates the preparation of2-[1′-(3-methanesulfonyl-benzoyl)-[1,4′]bipiperidinyl-4-yloxy]-5-trifluoromethyl-benzonitriletrifluoroacetate (Compound 291 of Table IV).

The product of Method E (183 mg, 0.5 mmol) was dissolved in DMSO (2 ml)and treated with sodium hydride (22 mg 1 equiv. of 60%) under an inertatmosphere. After stirring the mixture at RT for 1 hour,2-fluoro-5-trifluoromethyl-benzonitrile (1 equiv.) was added. Afterstirring at RT for 24 hours, the reaction mixture was acidified (glacialacetic acid) and filtered. The filtrate was purified by RPHPLC.(MeOH/aqueous TFA, Symmetry column) to give the product as thetrifluoroacetate salt (0.06 g; m.pt. 110-111° C.).

¹H NMR (400 MHz, DMSO-D6) δ1.0-3.8 (m, 20 H), 4.5-5.3 (m, 2H), 7.5 (d,1H), 7.75 (m, 3H), 8.02 (m, 2H).

EXAMPLE 15

This Example illustrates the preparation of(3-methanesulfonyl-phenyl)-[4-(6-methyl-pyridin-2-yloxy)-[1,4′]bipiperidinyl-1′-yl]-methanonetrifluoroacetate (Compound 292 of Table IV).

The product of Method E (1 mmol) and potassium tert-butoxide (2 mmol )were stirred together in dry THF (20 ml) at RT. After 10 mins2-fluoro-6-methyl-pyridine (1 mmol) was added and the reaction mixturestirred at reflux overnight. The reaction mixture was cooled, dilutedwith water and extracted into ethyl acetate (3×50 ml). The combinedextracts were dried (MgSO₄) and evaporated. The residue was purified byRPHPLC. (MeOH/aqueous TFA, Symmetry column) to give the product as thetrifluoroacetate salt (0.03 g; m.pt. 61-62° C.).

¹H NMR (400 MHz, DMSO-D6) δ1.6-3.8 (m, 15H), 2.4 (s, 3H), 3.3 (s, 3H),4.5-5.4 (m, 3H), 6.6 (m, 1H), 6.02 (dd, 1H), 7.6 (q, 1H), 7.82 (m, 2H),7.95 (s, 1H), 8.02 (m, 1H), 9.7 (bs, 1H)

EXAMPLE 16

This Example illustrates the preparation ofN-{3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide(Compound 583 of Table I).

To(3-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone(0.1 33 g) in pyridine (2 mL) was added methanesulfonyl chloride (0.024ml) and the reaction left to stir for 5 minutes. The solvent wasevaporated, water (0.5 mL) added and the solvent re-evaporated.Purification by RPHPLC (with a gradient eluent system (25% MeCN/NH₄OAcaq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) gave the title compound (0.050g; m.pt. 94-95° C.).

¹H NMR (399.978 MHz, CDCl₃) δ 1.59-2.09 (8H, m), 2.22 (2H, br s),2.54-2.60 (1H, m), 2.81 (2H, br s), 3.02 (5H, br s), 3.51-3.75 (1H, brm), 4.25-4.28 (1H, m), 4.29 (1H, br s), 6.70-7.52 (8H, m).

EXAMPLE 17

This Example illustrates the preparation ofN-{2-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-phenyl}-methanesulfonamide(Compound 587 of Table I).

To a solution of(2-amino-phenyl)-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-methanone(0.2 g) in pyridine (2 ml) at 0° C. was added methane sulphonyl chloride(0.039 ml). The mixture was allowed to warm to room temperature and thepyridine removed by evaporation. The residue was azeotroped with waterand the product purified by RPHPLC (Symmetry column, eluting 25% to 95%MeCN/0.1% NH₄OAc aq at 20 ml/min over 6 minutes) to give the product asa colourless solid (0.09 g).

¹H NMR: (399.978 MHz, CDCl₃) δ 1.49-1.69 (5H, m), 1.77-1.84 (2H, m),1.87-1.94 (1H, m), 1.95-2.02 (2H, m), 2.43-2.50 (2H, m), 2.59 (1H, tt),2.78-2.84 (2H, m), 2.87-3.03 (1H, m), 3.08 (3H, s), 3.17 (1H, sextet),4.27 (1H, septet), 6.75 (1H, dd), 6.99 (1H, d), 7.15 (1H, td), 7.24 (1H,d), 7.31 (1H, d), 7.43 (1H, td), 7.62 (1H, d).

EXAMPLE 18

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(1-methanesulfonyl-1H-indol-3-yl)-methanonehydrochloride (Compound 592 of Table I).

To a solution of Compound 471 of Table I (0.17 g) in dimethylformamide(3 ml) at 0° C. under an atmosphere of nitrogen, was added sodiumhydride (0.014 g of a 60% suspension in oil). The mixture was stirredfor 5 minutes then methanesulphonyl chloride (0.027 ml in 1 ml ofdimethylformamide) was added and then mixture allowed to warm to roomtemperature over 12 hours. The reaction mixture was partitioned betweendichloromethane (10 ml) and water (10 ml). The organic layer wasseparated, dried (MgSO₄) and the solvent removed by evaporation. Theresidue was purified by RPHPLC (Symmetry, 25% to 95% MeCN/0.1% NH₄OAc aqover 6 minutes, 20 ml/min, 220 nm) to give a colourless solid (0.062 g;m.pt. 173-175° C.).

¹H NMR: (299.944 MHz DMSO-D6) δ 1.72-1.87 (2H, m), 2.01-2.34 (5H, m),2.48-2.55 (1H, m), 2.98-3.13 (2H, m), 3.13-3.27 (2H, m), 3.39-3.47 (2H,m), 3.53-3.62 (2H, m), 3.64 (3H, s), 4.35-4.58 (1H, m), 4.65-4.76 (1H,m), 7.12 (1H, dd), 7.39-7.48 (2H, m), 7.52 (1H, t), 7.61 (1H, t), 7.79(1H, d), 7.88 (1H, s), 7.95 (1H, d).

EXAMPLE 19

This Example illustrates the preparation of1-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-2-phenyl-3-piperazin-1-yl-propan-1-one(Compound 595 of Table I).

Compound 575 of Table I (0.178 g) was treated with 6N hydrochloric acid(5 ml) and stirred at room temperature for 24 hours. 2N Sodium hydroxidesolution was added and the reaction mixture extracted with ethylacetate. The organic extracts were combined, washed with water, dried(MgSO₄) and evaporated to give a white solid. Purification was byreverse phase HPLC (with a gradient eluent system (25% MeCN/NH₄OAc aq(0.1%) to 95% MeCN//NH4OAcaq (0.1%)). (Any excess NH₄OAc was removed bydissolving the compound in ethyl acetate and washing with aqueoussaturated NaHCO₃ followed by drying of the organics with MgSO₄ andevaporation of solvent.) The title compound was a white solid (0.087 g).

1H NMR (399.98 MHz, DMSO-D6) δ 1.20-1.95 (9H, m), 2.10-2.53 (9H, m),2.59-2.65 (2H, m), 2.70-2.77 (1H, m), 2.89-3.12 (4H, m), 4.02-4.47 (4H,m), 6.89-7.00 (1H, m), 7.16-7.32 (6H, m), 7.44-7.52 (1H, m).

EXAMPLE 20

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-1-oxy-[1,4′]bipiperidinyl-1′-yl]-(3-methanesulfonyl-phenyl)-methanone.

The product Example 10 (0.100 g) in dichloromethane (5 ml) was treatedwith m-chloroperbenzoic acid (0.043 g) and the reaction stirred at roomtemperature for 0.5 hours. Saturated aqueous sodium hydrogencarbonatewas added and the reaction mixture extracted with dichloromethane. Thecombined organic extracts were washed with water, dried (MgSO₄) andevaporated to give a brown foam. Purification by RPHPLC (with a gradienteluent system (25% MeCN/NH4OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%))gave the title compound as a white solid (0.021 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 1.70-2.91 (15H, m), 3.24-3.44 (3H, m),3.55-3.68 (1H, m), 4.55-4.76 (2H, m), 6.99-7.06 (1H, m), 7.29-7.33 (1H,m), 7.53 (1H, dd), 7.71-7.79 (2H, m), 7.93 (1H, s), 7.99-8.05 (1H, m).

EXAMPLE 21

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone(Compound 1 of Table I).

To a solution of 4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.1 g, seestep b of Example 2) in dichloromethane (5 ml) and triethylamine (0.2ml) was added benzoyl chloride (0.045 ml) and the reaction mixture wasstirred for 2 hours. The mixture was washed with water, dried (MgSO₄),filtered and the solvents evaporated to leave a gum. Purification byRPHPLC [with an eluent system (50% MeCN/0.1%NH₄OAc aq), any excessNH₄OAc was removed by dissolving the compound in ethyl acetate andwashing with aqueous saturated NaHCO₃ followed by drying of the organicswith MgSO₄ and evaporation of solvent] and trituration of the resultingproduct with diethyl ether gave a solid which was filtered and dried togive the title compound (0.120 g; m.pt. 122° C.).

¹H NMR (299.944 MHz CDCl₃) δ 1.42-1.62 (2H, m), 1.78-1.82 (3H, m),1.95-2.01 (3H, m), 2.39-2.69 (3H, m), 2.69-3.09 (4H, m), 3.63-3.95(1H,m), 4.24-4.29 (1H, m), 4.62-4.89 (1H, m), 6.73-6.77 (1H, m), 6.99(1H, d), 7.26-7.29 (1H, m), 7.39 (5H, s).

EXAMPLE 22

This Example illustrates the preparation of[4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone(Compound 4 of Table V).

Step 1: 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acidtert-butyl ester

4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester(11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together inacetonitrile (200 ml) and potassium carbonate (8.86 g) was added. Themixture was heated at reflux for 18 hours after which water was addedand the resulting mixture extracted with dichloromethane. The organicextracts were combined, washed with water, dried (MgSO₄) and evaporatedto give the sub-title compound (14.58 g).

¹H NMR (299.944 MHz, CDCl₃) δ 1.45 (9H, s), 1.49-1.62 (2H, m), 1.87-1.96(2H, m), 2.89-2.98 (2H, m), 3.16-3.26 (1H, m), 3.91-4.01 (2H, m),7.21-7.57 (3H, m)

Step 2: 4-(3,4-dichloro-benzenesulfonyl)-piperidine-1-carboxylic acidtert-butyl ester

The product from Step 1 (1 g) and m-chloroperbenzoic acid (1.19 g) werestirred at ambient temperature in dichloromethane (10 ml) for 18 hours.Sodium metabisulphite (1.19 g) in water (5 ml) was added and stirringwas continued for 0.5 hours after which the reaction mixture wasextracted with dichloromethane. The combined organics were washed withsaturated sodium bicarbonate solution, dried (MgSO₄) and evaporated togive the sub-title compound (0.34 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.45 (9H, s), 1.56-1.65 (2H, m), 1.94-2.00(2H, m), 2.62-2.70 (2H, m), 3.01-3.09 (1H, m), 4.21-4.30 (2H, m),7.66-7.70 (2H, m), 7.93-7.98 (1H, m).

Step 3: 4-(3,4-dichloro-benzenesulfonyl)-piperidine

The product of step 2 was deprotected following the procedure of Example1 step b. ¹H NMR (299.944 MHz, CDCl₃) δ 1.64-1.71 (2H, m), 1.96-2.05(2H, m), 2.55-2.64 (2H, m), 2.99-3.10 (1H, m), 3.19-3.27 (2H, m),7.66-7.71 (2H, m), 7.92-7.98 (1H, m).

Step 4:4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

The product of step 3 was used in a reductive amination with4-oxo-piperidine-1-carboxylic acid tert-butyl ester following theprocedure of Example 2 step a.

Step 5: 4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl

The product of step 4 was deprotected following the procedure of Example2 step b. ¹H NMR (299.946 MHz, DMSO-D6) δ 1.22-1.61 (7H, m), 1.77-1.83(2H, m), 2.09-2.16 (1H, m), 2.25-2.45 (3H, m), 2.87-2.98 (4H, m),3.35-3.43 (1H, 7.81 (1H, dd), 7.96 (1H, d), 8.05 (1H, d)

Step 6:[4-(3,4-dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-(4-methanesulfonyl-phenyl)-methanone

The product of step 5 was coupled to 4-methanesulfonyl-benzoic acidfollowing the procedure of Example 2 step c.

1H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.62 (5H, m), 1.70-1.85 (4H, m),2.13 (3H, t), 2.72-3.04 (4H, m), 3.27 (3H, s), 3.37-3.48 (1H, m),4.44-4.52 (1H, m), 7.63 (2H, d), 7.81 (1H, dd), 7.95-8.00 (3H, m), 8.06(1H, d).

[4-(3,4-Dichloro-benzenesulfonyl)-[1,4′]bipiperidinyl-1′-yl]-phenyl-methanone(Compound 5 of Table V). The product of step 5 was coupled to benzoicacid following the procedure of Example 2 step c. ¹H NMR (299.946 MHz,DMSO-D6) δ 1.31-1.69 (5H, m), 1.82 (3H, d), 2.15 (2H, d), 2.69-2.75 (1H,m), 2.90-2.97 (4H, m), 3.33-3.43 (1H, m), 3.48-3.63 (1H, m), 4.42-4.53(1H, m), 7.39 (5H, dt), 7.81 (1H, dd), 7.96 (1H, d), 8.06 (1H, d).

EXAMPLE 23

This Example illustrates the preparation of3-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-1-ethyl-7-methyl-1H-[1,8]naphthyridin-4-one (Compound 534 of Table I).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b ofExample 2) was dissolved in dichloromethane (5 ml),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425g), 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (0.155 g) and triethylamine (0.254 ml) were added. After 16 hoursat room temperature dichloromethane and aqueous NaHCO₃ solution wereadded. The product was extracted with dichloromethane, the combinedorganic extracts were washed with water, dried with MgSO₄ andconcentrated. Purification by RPHPLC (with a gradient eluent system (45%MeCN/NH₄OAc aq (0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) %)) (any excessNH4OAc was removed by dissolving the compound in ethyl acetate andwashing with aqueous saturated NaHCO₃ followed by drying of the organicswith Magnesium sulfate and evaporation of solvent) gave the titlecompound (0.184 g; m.pt. 189-190° C.)

MS: APCI⁺(M+H) 543

¹H NMR (299.946 MHz, DMSO-D6) δ 1.37 (3H, t), 1.47-1.69 (5H, m),1.78-1.84 (1H, m), 1.89-1.97 (2H, m), 2.36-2.41 (2H, m), 2.49-2.56 (1H,m), 2.66 (3H, s), 2.70-2.79 (3H, m), 2.95-3.04 (1H, m), 3.52-3.59 (1H,m), 4.38-4.57 (4H, m), 6.95-6.99 (1H, m), 7.22-7.24 (1H, m), 7.35-7.40(1H, m), 7.46-7.51 (1H, m), 8.37 (1H, s), 8.43-8.45 (1H, m).

EXAMPLE 24

This Example illustrates the preparation of4-[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbonyl]-2H-isoquinolin-1-one(Compound 572 of Table I).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b ofExample 2) was dissolved in dichloromethane (5 ml),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425g), 1-oxo-1,2-dihydro-isoquinoline4-carboxylic acid (0.126 g) andtriethylamine (0.254 ml) were added. After 16 hours at room temperaturedichloromethane and aqueous NaHCO₃ solution were added. The product wasextracted with dichloromethane, the combined organic extracts werewashed with water, dried with MgSO₄ and concentrated. Purification byRPHPLC (with a gradient eluent system (45% MeCN/NH₄OAc aq (0.1%) to 95%MeCN//NH₄OAc aq (0.1%))) (any excess NH4OAc was removed by dissolvingthe compound in ethyl acetate and washing with aqueous saturated NaHCO₃followed by drying of the organics with Magnesium sulfate andevaporation of solvent) gave the title compound (0.153 g).

MS: APCI⁺(M+H) 500

¹H NMR (299.944 MHz CDCl₃) δ 1.37-1.66 (2H, m), 1.73-1.88 (3H, m),1.93-2.05 (3H, m), 2.41-2.51 (2H, m), 2.52-2.63 (1H, m), 2.75-2.86 (2H,m), 2.86-3.09 (2H, m), 3.71-3.90 (1H, m), 4.23-4.32 (1H, m), 4.77-4.93(1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.27-7.32 (3H, m), 7.54-7.67 (1H,m), 7.57 (1H, t), 7.74 (1H, t), 8.46 (1H, d).

EXAMPLE 25

This Example illustrates the preparation of[4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone(Compound 579 of Table I).

Step a: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

To a solution of 2-amino-5-fluoropyridine (1.12 g) in diethyl ether (25ml) was added ethyl bromopyruvate (1.25 ml). the mixture was stirred for1 hour. The resultant solid was filtered off, suspended in ethanol andheated at reflux for 4 hours. The solvent was removed by evaporation andthe residue partitioned between ethyl acetate (100 ml) and aqueoussodium bicarbonate solution (100 ml). The organic layer was separated,dried, (magnesium sulfate) and the solvent removed by evaporation. Theresidue was purified by flash chromatography (silica) eluting with ethylacetate: hexane (3:1) to give the sub-title compound as a colourlesssolid (1.12 g).

MS: ES⁺(M+H) 209

¹H NMR (399.98 MHz, CDCl₃) δ 1.44 (3H, t), 4.46 (2H, q), 7.19 (1H, ddd),7.68 (1H, dd), 8.07-8.09 (1H, m), 8.19 (1H, s).

Step b: 6-Fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid

A solution of 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethylester (1 g) in 4N HCl was refluxed for 4 hours. The solvent wasevaporated to give the sub-title compound as a white solid (0.86 g).

MS: ES⁺(M+H) 181

¹H NMR (399.98 MHz, DMSO-D6) δ 7.81-7.89 (2H,m), 8.71 (1H,s), 9.03(1H,s).

Step c:[4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-yl]-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-methanone

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see step b ofExample 2) was dissolved in dichloromethane (5 ml),bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PYBROP™; 0.425g), 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (0.126 g) andtriethylamine (0.254 ml) were added. After 16 hours at room temperaturedichloromethane and aqueous NaHCO₃ solution were added. The product wasextracted with dichloromethane, the combined organic extracts werewashed with water, dried with MgSO₄ and concentrated. Purification byreverse phase HPLC (with a gradient eluent system (45% MeCN/NH₄OAc aq(0.1%) to 95% MeCN//NH₄OAc aq (0.1%)) (any excess NH₄OAc was removed bydissolving the compound in ethyl acetate and washing with aqueoussaturated NaHCO₃ followed by drying of the organics with magnesiumsulfate and evaporation of solvent) gave the title compound (0.104 g).

MS: APCI⁺(M+H) 491

¹H NMR (399.978 MHz, CDCl₃) δ 1.61 (1H, qd), 1.75-2.02 (7H, m),2.42-2.51 (2H, m), 2.59-2.67 (1H, m), 2.75-2.86 (3H, m), 3.12-3.21 (1H,m), 4.23-4.29 (1H), 4.76-4.85 (1H, m), 5.23-5.32 (1H, m), 6.75 (1H, dd),6.99 (1H, d), 7.16 (1H, ddd), 7.30 (1H, d), 7.58 (1H, dd), 8.07 (2H, s).

EXAMPLE 26

This Example illustrates the preparation of4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidphenylamide (Compound 309 of Table IV).

Phenylisocyanate(0.078 ml) was added to a solution of4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidine (0.2 g, see Example 2 stepb) in dichloromethane (5 ml). The mixture was stirred at 23° C. for 16hours. The resulting precipitate was filtered, washed withdichloromethane (2×5 ml) then crystallised from acetonitrile to affordthe title compound as a solid (0.2 g; melting point 215-216° C.).

¹H NMR (DMSO-D6) δ 1.35 (2H, qd), 1.53-1.62 (2H, m), 1.72-1.78 (2H, m),1.89-1.96 (2H, m), 2.36-2.42 (2H, m), 2.44-2.52 (1H, m), 2.72-2.78 (4H,m), 4.15 (2H, d), 4.39-4.45 (1H, m), 6.91 (1H, tt), 6.98 (1H, dd),7.19-7.23 (2H, m), 7.25 (1H, d), 7.43-7.46 (2H, m), 7.49 (1H, d), 8.46(1H, s).

4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carbothioic acidphenylamide was prepared using the methodology of Example 26 andemploying phenylisothiocyanate, (melting point 162-163° C.). ¹H NMR:(DMSO-d6) δ 1.39-1.49 (2H, m), 1.53-1.62 (2H, m), 1.79 (2H, d),1.89-1.96 (2H, m), 2.39 (2H, t), 2.54-2.63 (1H, m), 2.73-2.80 (2H, m),3.04 (2H, t), 4.39-4.46 (1H, m), 4.72 (2H, d), 6.98 (1H, dd), 7.06-7.10(1H, m), 7.23-7.30 (5H, m), 7.49 (1H, d), 9.24 (1H, s).

EXAMPLE 27

This Example illustrates the preparation of4-(3,4-dichloro-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acid(3-methanesulfonyl-phenyl)-amide (Compound 54 of Table IV).

Hydrogen peroxide (100 μl, 30%) was added to a cooled (0° C.) solutionof Compound 312 of Table IV (0.13 g) in trifluoroacetic acid(1ml). Themixture was allowed to reach ambient temperature and stirred for afurther 1 hour. The solution was quenched with water(5 ml), basified topH11 with 2M sodium hydroxide solution and extracted with ethyl acetate.The organic solution was separated, washed with water(2×5 ml), dried(MgSO₄), filtered and the filtrate evaporated to leave a gum. The gumwas dissolved in acetonitrile and purified by RPHPLC (Nova Pak column)eluting with acetonitrile/0.1% ammonium acetate aq (1:1). The requiredfractions were evaporated and then lyophilised to give the title compundas a colourless powder (0.03 g).

¹H NMR (DMSO-D6) δ 1.31-1.42 (2H, m), 1.53-1.62 (2H, m), 1.77 (2H, d),1.89-1.96 (2H, m), 2.36-2.43 (3H, m), 2.74-2.82 (4H, m), 3.16 (3H, s),4.18 (2H, d), 4.42 (1H, septet), 6.98 (1H, dd), 7.25 (1H, d), 7.44-7.52(3H, m), 7.80-7.83 (1H, m), 8.09 (1H, t), 8.90 (1H, s).

Selected proton NMR data and/or melting point data are provided forcertain further compounds in Tables VI and VII below.

TABLE VI Compound (Table no.) NMR data  3 (I) δ(D₂O) 1.97-1.69(2H, m),2.21-2.08(2H, m), 2.51-2.23(4H, m), 3.07-2.96(1H, m), 3.31-3.17(2H, m),3.45-3.32(2H, m), 3.56-3.45 (1H, m), 3.75-3.56(2H, m), 4.88-4.70(3H, m),7.07-7.02(1H, m), 7.36-7.30(1H, m), 7.46-7.37(1H, m), 7.55(2H, d),7.74-7.72(1H, m)  8 (I) δ(CDCl₃) 1.67-1.41(2H, m), 1.86-1.76(3H, m),2.04-1.93(3H, m), 2.51-2.42(3H, m), 2.62-2.56(1H, m), 2.88-2.76(3H, m),3.06(1H, t), 3.66(1H, d), 4.28(1H, septet), 4.76(1H, d), 6.75(1H, dd),6.99(1H, d), 7.31(1H, d), 7.56(2H, d), 8.28(2H, d)  18 (I) δ(CD₃OD)1.59-1.41(2H, m), 1.83-1.68(2H, m), 2.08-1.93(4H, m), 2.56-2.48(4H, m),2.68-2.61(1H, m), 2.91-2.80(3H, m), 3.15-3.02 (1H, m), 3.71-3.57(1H, m),4.23-4.14(1H, m), 4.40(1H, septet), 4.50 (3H, s), 4.75-4.57(1H, m),6.91(1H, dd), 7.12(1H, d), 7.40(1H, d), 7.66(2H, d), 8.04(2H, d)  36 (I)δ(CD₃OD) 1.62-1.42(2H, m), 1.94-1.72(3H, m), 2.11-1.98(3H, m),2.61-2.52(2H, m), 2.95-2.82(3H, m), 3.15(1H, t), 3.68-3.63(1H, m),4.42(1H, septet), 4.71-4.67(2H, m), 6.91(1H, dd), 7.11(1H, d), 7.40(1H,d), 7.60(2H, d), 7.86(2H, d)  37 (I) δ(CD₃OD) 2.06-1.76(3H, m),2.45-2.12(5H, m), 3.05-2.88(1H, m), 3.42-3.25(3H, m), 3.71-3.50(2H, m),3.93-3.74(1H, m), 4.63(1H, septet), 4.94-4.82(2H, m), 7.03-6.95(1H, m),7.24(1H, dd), 7.47-7.42 (1H, m), 7.71-7.66(1H, m), 7.78(1H, td),7.90-7.86(2H, m) 149 (I) δ(CDCl₃) 1.50-1.27(2H, m), 1.90-1.75(5H, m),2.02-1.92(2H, m), 2.56-2.39(4H, m), 2.63(1H, t), 2.81-2.72(2H, m),3.09-3.01(3H, m), 3.82(2H, s), 3.91(1H, d), 4.25(1H, septet), 4.67(1H,d), 6.75(1H, dd), 6.99(1H, d), 7.31(1H, dd), 7.45(2H, d), 7.90(2H, d)203 (I) δ(DMSO-D6) 1.61-1.44(2H, m), 2.24-2.01(4H, m), 2.61-2.53(2H, m),3.16-2.99(2H, m), 3.60-3.30(5H, m), 3.67(2H, s), 3.77(3H, s), 4.13(1H,d), 4.53(1H, d), 4.69-4.60(1H, m), 7.05(1H, ddd), 7.14(1H, d),7.42-7.25(3H, m), 7.55(2H, dd), 10.98-10.78(3H, m) 205 (I) δ((CD₃)₂CO)1.26(2H, quintet), 1.76-1.58(4H, m), 1.98-1.90(2H, m), 2.42-2.35(2H, m),2.58-2.45(2H, m), 2.81-2.71(2H, m), 3.00(1H, t), 3.70(2H, s), 4.00(1H,d), 4.39(2H, septet), 4.51(1H, d), 6.92(1H, dd), 7.07-7.01(2H, m),7.13(1H, d), 7.30-7.25(2H, m), 7.40(1H, d) 220 (I) δ(DMSO-D6)1.58-1.44(2H, m), 2.28-1.97(5H, m), 2.59-2.53(2H, m), 3.18-2.93(3H, m),3.34-3.25(1H, m), 3.51-3.36(2H, m), 3.66-3.56 (2H, m), 4.11(1H, d),4.53(1H, d), 4.64(1H, septet), 6.92-6.82 (2H, m), 6.99(1H, d),7.10-7.03(1H, m), 7.36(1H, dd), 7.55(1H, ddd), 10.99-10.87(1H, m) 225(I) δ((CD₃)₂CO) 1.71-1.51(2H, m), 2.13-2.08(2H, m), 2.40-2.21(3H, m),2.61-2.54(1H, m), 3.05(1H, t), 3.55-3.15(6H, m), 3.69-3.61 (2H, m),4.16(1H, d), 4.76-4.63(2H, m), 4.91-4.86(1H, m), 6.78-6.76 (2H, m),7.12-7.02(3H, m), 7.32(1H, dd), 7.51(1H, dd) 244 (I) δ(DMSO-D6)1.55-1.42(2H, m), 2.25-1.96(6H, m), 2.66-2.54(2H, m), 3.14-2.96(2H, m),3.32-3.26(1H, m), 3.51-3.35(2H, m), 3.62 (3H, s), 3.71-3.64(2H, m),3.74(6H, s), 4.14(1H, d), 4.54(1H, d), 4.66-4.58 (1H, m), 6.53(2H, s),7.04(1H, dd), 7.35(1H, d), 7.54(1H, tt) 253 (I) δ(CDCl₃) 1.47-1.19(2H,m), 2.00-1.76(6H, m), 2.62-2.37(4H, m), 2.80-2.70(2H, m), 2.98(1H, t),3.65(2H, s), 3.88(3H, s), 3.92-3.89 (1H, m), 4.25(1H, septet), 4.68(1H,d), 6.77-6.72(1H, m), 6.89(1H, d), 6.94-6.92(2H, m), 7.01-6.96(2H, m),7.30(1H, dd) 258 (I) δ(DMSO-D6) 1.40-1.26(3H, m), 1.78-1.59(5H, m),1.98-1.92(1H, m), 2.17(3H, s), 2.21(3H, s), 2.45-2.37(2H, m),2.60-2.48(3H, m), 3.01(1H, t), 3.70-3.57(2H, m), 3.89(1H, d), 4.39(1H,septet), 4.55(1H, d), 7.00(1H, d), 7.13(1H, d), 7.41(1H, d),7.95-7.89(3H, m) 267 (I) δ(CDCl₃) 1.74-1.61(2H, m), 2.21-2.09(3H, m),2.32-2.25(1H, m), 2.48(1H, t), 2.67-2.53(2H, m), 2.89(1H, t),3.31-3.05(5H, m), 3.71 (4H, s), 3.82(2H, s), 4.08(1H, d), 4.59-4.53(1H,m), 4.94(1H, d), 6.89 (1H, dd), 6.93(1H, dd), 6.97(1H, d), 7.34(1H, d),7.40(1H, d), 7.58-7.54 (1H, m), 268 (I) δ(CDCl₃) 1.24(1H, dq), 1.41(1H,dq), 1.88-1.72(4H, m), 2.00-1.91 (2H, m), 2.53-2.37(3H, m), 2.59(1H,dt), 2.78-2.70(2H, m), 2.98 (1H, t), 3.73(2H, s), 3.89(1H, d), 4.24(1H,septet), 4.68(1H, d), 6.74 (1H, dd), 7.03-6.91(4H, m), 7.29-7.25(1H, m),7.30(1H, d) 272 (I) δ(CDCl₃) 1.18(1H, dq), 1.40(1H, dq), 1.86-1.68(4H,m), 2.00-1.91 (2H, m), 2.43-2.35(2H, m), 2.48(1H, td), 2.57(1H, dt),2.77-2.68 (2H, m), 2.95(1H, dt), 3.74(2H, s), 3.91(1H, d), 4.23(1H,septet), 4.69 (1H, d), 6.74(1H, dd), 6.98(1H, d), 7.35-7.23(6H, m) 274(I) δ(DMSO-D6) 1.74-1.59(5H, m), 1.77(3H, dq), 2.65-2.36(4H, m),2.86-2.74 (6H, m), 2.95(1H, t), 3.74(3H, s), 3.93(1H, d), 4.40(1H,septet), 4.53(1H, d), 6.73-6.70(1H, m), 6.80-6.78(2H, m), 6.93(1H, dd),7.18-7.13 (2H, m), 7.41(1H, d) 276 (I) δ((CD₃)₂CO) 1.63-1.51(2H, m),2.02-1.98(2H, m), 2.21-2.15(2H, m), 2.58-2.31(4H, m), 2.96(1H, t),3.40-3.03(4H, m), 3.60-3.49 (2H, m), 3.72(3H, s), 4.02(1H, d),4.63-4.55(1H, m), 4.77-4.72(1H, m), 6.76(1H, t), 6.84(1H, d),6.96-6.93(1H, m), 7.03(1H, d), 7.11-7.07 (1H, m), 7.16-7.15(1H, m),7.37-7.31(1H, m) 286 (I) δ(CD₃OD) 1.90-1.63(2H, m), 2.49-2.05(6H, m),3.28-2.87(7H, m), 3.84-3.44(5H, m), 4.69-4.56(1H, m), 4.85-4.78(2H, m),7.04-6.94 (1H, m), 7.28-7.21(1H, m), 7.45(1H, t), 7.60-7.55(3H, m),7.64-7.61 (1H, m), 7.66(1H, t), 7.77-7.73(2H, m), 7.85-7.81(2H, m) 291(I) δ(CD₃OD) 1.98-1.71(3H, m), 2.46-2.11(5H, m), 3.18-2.98(1H, m),3.45-3.26(2H, m), 3.70-3.46(4H, m), 3.86(3H, s), 4.66-4.56(1H, m),4.84-4.80(2H, m), 7.04-6.94(3H, m), 7.27-7.20(1H, m), 7.47-7.42 (3H, m)293 (I) δ(CD₃OD) 1.88-1.73(2H, m), 2.22-1.92(5H, m), 2.31(1H, d),2.87-2.79 (1H, m), 3.06-2.97(1H, m), 3.17(3H, s), 3.57-3.31(5H, m),4.55-4.44 (1H, m), 4.73-4.65(2H, m), 6.92-6.82(1H, m), 7.12(1H, td),7.40-7.31(2H, m), 7.63(1H, dt), 7.75-7.68(1H, m), 7.99(1H, dt) 294 (I)δ(CD₃OD) 1.98-1.70(2H, m), 2.45-2.08(6H, m), 2.97(1H, t), 3.21 (3H, s),3.41-3.21(3H, m), 3.72-3.49(3H, m), 4.67-4.56(1H, m), 4.95-4.81(2H, m),7.03-6.94(1H, m), 7.27-7.20(1H, m), 7.47-7.42 (1H, m), 7.74-7.62(1H, m),8.02(1H, ddd), 8.13(1H, dd) 295 (I) δ(CD₃OD) 2.04-1.74(3H, m),2.36-2.12(4H, m), 2.48-2.40(1H, m), 3.03-2.87(1H, m), 3.43-3.15(3H, m),3.80-3.47(3H, m), 4.68-4.58 (1H, m), 4.85-4.80(2H, m), 5.13(2H, s),7.03-6.96(1H, m), 7.27-7.21 (1H, m), 7.46-7.42(1H, m), 7.63-7.56(3H, m),7.79-7.69(4H, m), 8.12(1H, d) 296 (I) δ(CD₃OD) 2.46-1.75(8H, m),2.96(1H, t), 3.32(2H, s), 3.72-3.19 (4H, m), 3.97-3.92(1H, m),4.69-4.56(1H, m), 4.98-4.79(2H, m), 7.03-6.94(1H, m), 7.24(1H, d),7.69-7.35(10H, m) 297 (I) δ(CD₃OD) 1.66-1.51(2H, m), 1.89-1.69(3H, m),2.08-1.96(3H, m), 2.71-2.50(3H, m), 3.01-2.81(3H, m), 3.24-3.10(1H, m),3.84-3.71 (1H, m), 4.46-4.38(1H, m), 4.79-4.67(1H, m), 6.92(1H, dd),7.14 (1H, d), 7.41(1H, d), 7.81(1H, dd), 8.39(1H, d), 8.71(1H, s) 298(I) δ(CD₃OD) 1.33(3H, t), 1.62-1.41(2H, m), 1.95-1.74(3H, m), 2.11-1.98(3H, m), 2.73-2.52(3H, m), 2.95-2.79(3H, m), 3.03(2H, q), 3.26-3.09 (1H,m), 3.93-3.78(1H, m), 4.48-4.39(1H, m), 4.78-4.56(1H, m), 6.91(1H, dd),7.11(1H, d), 7.42-7.34(5H, m) 299 (I) δ(CD₃OD) 1.99-1.72(3H, m),2.36-2.11(4H, m), 2.44(1H, d), 3.06-2.87 (1H, m), 3.42-3.23(2H, m),3.71-3.46(4H, m), 3.95-3.77(1H, m), 4.67-4.55(1H, m), 4.84-4.80(1H, m),7.03-6.94(1H, m), 7.27-7.20 (1H, m), 7.47-7.43(1H, m), 7.66-7.61(2H, m),7.87-7.81(2H, m) 300 (I) δ(CD₃OD) 1.96-1.72(3H, m), 2.33-2.09(4H, m),2.46-2.41(1H, m), 3.02-2.87(1H, m), 3.43-3.22(3H, m), 3.72-3.47(3H, m),3.93-3.78 (1H, m), 4.66-4.56(1H, m), 4.84-4.80(1H, m), 7.03-6.94(1H, m),7.28-7.21(1H, m), 7.47-7.43(1H, m), 7.59(2H, d), 7.83(2H, d) 301 (I)(500.076MHz, DMSO-D6) δ 1.33-1.44(m, 2H), 1.55-1.60(m, 2H), 1.66-1.73(m,1H), 1.78-1.86(m, 1H), 1.91(s, 3H), 1.91-1.96(m, 2H), 2.05(s, 3H),2.39(t, 2H), 2.55(t, 1H), 2.74-2.79(m, 3H), 2.94-3.04(m, 1H),3.56-3.66(m, 1H), 4.42(septet, 1H), 4.45-4.52(m, 1H), 6.98(dd, 2H),7.02(d, 2H), 7.25(d, 1H), 7.35(t, 1H), 7.49(d, 1H), 7.58(d, 1H), 7.66(s,1H) 302 (I) (500.076MHz, DMSO-D6) δ 1.36(dq, 2H), 1.54-1.60(m, 2H),1.72-1.75 (m, 2H), 1.91(s, 3H), 1.91-1.95(m, 2H), 2.05(s, 3H), 2.39(t,2H), 2.74-2.78(m, 2H), 2.80-2.87(m, 1H), 4.05-4.19(m, 2H), 4.42 (septet,1H), 5.22(s, 2H), 6.58(d, 1H), 6.97-6.99(m, 2H), 7.00(s, 1H), 7.25(d,1H), 7.49(d, 1H) 303 (I) (500.076MHz, DMSO-D6) δ 1.54-1.63(m, 4H),1.69-1.82(m, 4H), 1.91-1.96(m, 2H), 1.91(s, 3H), 2.35-2.44(m, 2H),2.73-3.04(m, 7H), 4.39-4.46(m, 2H), 6.48-6.49(m, 1H), 6.98(d, 1H),7.02-7.07 (m, 3H), 7.26(s, 1H), 7.34(t, 1H), 7.49(d, 1H), 7.62(d, 1H)304 (I) (500.076MHz, DMSO-D6) δ 1.33(t, 3H), 1.36-1.43(m, 2H), 1.54-1.60(m, 2H), 1.70-1.80(m, 2H), 1.91-1.96(m, 2H), 1.91(s, 3H), 2.39 (t, 2H),2.51-2.55(m, 1H), 2.74-2.79(m, 2H), 3.79(s, 3H), 4.01-4.05 (m, 1H),4.02(q, 2H), 4.42(septet, 1H), 4.47-4.53(m, 1H), 6.94(s, 2H),6.97-6.99(m, 2H), 7.25(d, 1H), 7.49(d, 1H) 305 (I) (500.076MHz, DMSO-D6)δ 1.37-1.46(m, 2H), 1.54-1.61(m, 2H), 1.67-1.83(m, 2H), 1.91-1.96(m,2H), 1.91(s, 3H), 2.40(t, 2H), 2.53-2.58 (m, 1H), 2.74-2.80(m, 2H),2.99-3.10(m, 1H), 3.63-3.74(m, 1H), 4.42(septet, 1H), 4.46-4.54(m, 1H),6.29-6.30(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.43-7.44(m, 1H), 7.48(t,3H), 7.64(d, 2H) 306 (I) (500.076MHz, DMSO-D6) δ 1.22-1.40(m, 2H),1.54-1.61(m, 2H), 1.75(t, 2H), 1.91-1.96(m, 2H), 2.38(t, 2H),2.53-2.60(m, 1H), 2.71-2.77 (m, 2H), 3.03(t, 1H), 3.79(s, 2H),3.98-4.03(m, 1H), 4.36-4.40 (m, 1H), 4.40-4.45(m, 1H), 6.98(dd, 1H),7.25(d, 1H), 7.50(d, 1H), 8.34(s, 1H), 8.40(s, 1H), 8.57(d, 1H) 307 (I)(500.076MHz, DMSO-D6) δ 1.17-1.31(m, 2H), 1.53-1.59(m, 2H), 1.69(t, 2H),1.88-1.94(m, 2H), 2.35(t, 2H), 2.45-2.52(m, 1H), 2.68-2.74 (m, 2H),2.95(t, 1H), 3.50(s, 2H), 3.59(s, 3H), 4.06-4.10(m, 1H), 4.36-4.43(m,2H), 6.88(s, 1H), 6.97(dd, 1H), 7.25(d, 1H), 7.45(s, 1H), 7.49(d, 1H)308 (I) (500.076MHz, DMSO-D6) δ 1.03(dq, 1H), 1.18(dq, 1H), 1.49-1.58(m, 3H), 1.68(d, 1H), 1.83-1.90(m, 2H), 1.91(s, 3H), 2.23-2.30(m, 2H),2.41-2.49(m, 3H), 2.57-2.67(m, 2H), 2.90(t, 1H), 3.66(q, 2H), 4.01(d,1H), 4.38(septet, 1H), 4.43(d, 1H), 6.58(dd, 1H), 6.88(d, 1H), 6.96(dd,1H), 7.07(d, 1H), 7.12(d, 1H), 7.23(d, 1H), 7.49(d, 1H), 8.58 (s, 1H)309 (I) (500.076MHz, DMSO-D6) δ 1.46-1.56(m, 2H), 1.89-1.98(m, 2H),2.03-2.18(m, 4H), 2.23(d, 1H), 2.55-2.61(m, 1H), 3.02-3.17(m, 4H),3.42-3.51(m, 2H), 3.98(s, 2H), 4.16(d, 1H), 4.54(d, 1H), 4.60-4.66 (m,1H), 6.93-6.97(m, 1H), 7.01-7.09(m, 1H), 7.15(s, 1H), 7.25 (s, 1H),7.34-7.38(m, 1H), 7.54-7.58(m, 1H) 310 (I) (500.076MHz, DMSO-D6) δ1.11(t, 3H), 1.39-1.48(m, 2H), 1.55-1.60 (m, 2H), 1.65-1.72(m, 1H),1.81-1.87(m, 1H), 1.90-1.95(m, 2H), 1.90(s, 3H), 2.39(t, 2H),2.53-2.59(m, 1H), 2.74-2.83(m, 2H), 3.03-3.10(m, 1H), 3.36(q, 2H),3.47-3.55(m, 1H), 4.42(septet, 1H), 4.46-4.54(m, 1H), 6.98(dd, 1H),7.25(d, 1H), 7.49(d, 1H), 7.72-7.78 (m, 2H), 7.86(s, 1H), 7.96(d, 1H)311 (I) (500.076MHz, DMSO-D6) δ 0.92(t, 3H), 1.40-1.49(m, 2H), 1.55-1.64(m, 2H), 1.57(sextet, 2H), 1.65-1.73(m, 1H), 1.81-1.88(m, 1H), 1.91(s,3H), 1.91-1.96(m, 2H), 2.36-2.44(m, 2H), 2.54-2.61(m, 1H), 2.73-2.84(m,2H), 3.02-3.11(m, 1H), 3.45-3.53(m, 1H), 4.40-4.46 (m, 1H), 4.50-4.54(m,1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H), 7.72-7.78(m, 2H), 7.86(s,1H), 7.96(d, 1H) 312 (I) (500.076MHz, DMSO-D6) δ 0.98(d, 6H),1.39-1.49(m, 2H), 1.54-1.61 (m, 2H), 1.64-1.71(m, 1H), 1.81-1.87(m, 1H),1.90-1.95(m, 2H), 1.91(s, 3H), 2.02(septet, 1H), 2.39(t, 2H),2.53-2.59(m, 1H), 2.74-2.79(m, 2H), 3.03-3.11(m, 1H), 3.45-3.52(m, 1H),4.42 (septet, 1H), 4.47-4.53(m, 1H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d,1H), 7.71-7.77(m, 2H), 7.88(s, 1H), 7.98(d, 1H) 313 (I) (500.076MHz,DMSO-D6) δ 1.41-1.53(m, 2H), 1.54-1.62(m, 2H), 1.66-1.74(m, 1H),1.84-1.89(m, 1H), 1.91-1.96(m, 2H), 1.91(s, 3H), 2.36-2.44(m, 2H),2.54-2.62(m, 1H), 2.73-2.87(m, 4H), 3.10 (t, 1H), 3.50(s, 3H), 3.52(s,3H), 3.52-3.58(m, 1H), 4.40-4.46(m, 1H), 4.48-4.54(m, 1H), 6.97-7.00(m,1H), 7.23-7.29(m, 1H), 7.50 (d, 1H), 8.06(d, 1H), 8.16(s, 1H), 8.29(d,1H) 314 (I) (500.076MHz, DMSO-D6) δ 1.34(t, 3H), 1.35-1.41(m, 2H),1.54-1.60 (m, 2H), 1.74(d, 2H), 1.90-1.96(m, 2H), 1.90(s, 3H), 2.39(t,2H), 2.50-2.55(m, 1H), 2.73-2.79(m, 2H), 2.80-2.89(m, 1H), 4.01(q, 2H),4.08-4.19(m, 2H), 4.42(septet, 2H), 5.06(s, 2H), 6.62(d, 1H), 6.77(d,1H), 6.81(s, 2H), 6.98(dd, 1H), 7.25(d, 1H), 7.49(d, 1H) 315 (I)(DMSO-D6) δ 1.53-1.82(m, 2H), 2.02-2.36(m, 5H), 2.60-2.67(m, 1H),3.07-3.15(m, 2H), 3.31-3.38(m, 1H), 3.43-3.53(m, 2H), 4.12-4.19 (m, 4H),4.51(d, 1H), 4.68(septet, 1H), 4.85(s, 1H), 7.06(ddd, 1H), 7.37(dd, 1H),7.56(t, 1H), 7.94(d, 2H), 8.86(d, 2H), 11.47(s, 1H) 316 (I) (DMSO-D6) δ1.58-2.28(m, 4H), 2.67-2.84(m, 1H), 2.91-3.04(m, 2H), 2.97(s, 2H),3.06-3.26(m, 2H), 3.24-3.42(m, 1H), 3.44-3.67 (m, 3H), 3.57(s, 3H),4.55-4.77(m, 2H), 4.83(s, 1H), 7.00-7.09(m, 2H), 7.35-7.58(m, 5H) 317(I) (DMSO-D6) δ 1.52(dq, 2H), 1.74-1.92(m, 2H), 1.93-2.04(m, 4H),2.42-2.50(m, 2H), 2.55(tt, 1H), 2.77-2.85(m, 2H), 2.87-2.96(m, 2H),4.22-4.30(m, 3H), 6.69-6.74(m, 2H), 6.76(d, 1H), 6.99(d, 1H), 7.07(dd,1H), 7.16(dt, 1H), 7.29(s, 2H), 7.32(s, 1H) 318 (I) (DMSO-D6) δ 1.71(m,2H), 2.18(m, 3H), 2.70(s, 3H), 3.02(m, 1H), 3.15(m, 2H), 3.32(m, 3H),3.50(m, 2H), 4.63(m, 1H), 7.05(ddd, 1H), 7.36(m, 4H), 7.56(t, 1H),7.66(d, 1H), 8.11(s, 1H), 8.37(d, 1H) 319 (I) (DMSO-D6) δ 1.40(m, 2H),1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H), 2.40(m, 2H), 2.58(m, 1H), 2.79(m,2H), 2.87(m, 2H), 4.30(d, 2H), 4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H),7.25(d, 1H), 7.43(d, 1H), 7.49(d, 1H), 7.65(m, 2H) 321 (I) (DMSO-D6) δ1.67-1.78(m, 2H), 1.95-2.09(m, 3H), 2.18-2.27(m, 2H), 2.44(d, 3H),2.77-2.88(m, 1H), 3.08-3.19(m, 3H), 3.33-3.52 (m, 5H), 3.59-3.67(m, 1H),4.60-4.68(m, 1H), 4.84(s, 1H), 7.05 (ddd, 1H), 7.14-7.27(m, 1H),7.37(dd, 1H), 7.55(t, 1H), 7.61(q, 1H), 7.70-7.71(m, 2H), 7.78-7.80(m,1H), 7.86-7.89(m, 1H) 322 (I) (DMSO-D6) δ 1.65-1.80(m, 2H), 1.99-2.09(m,2H), 2.19-2.30(m, 3H), 2.77-2.90(m, 1H), 3.07-3.21(m, 3H), 3.30-3.37(m,3H), 3.47-3.57 (m, 2H), 3.59-3.71(m, 1H), 4.59-4.69(m, 1H), 4.82-4.86(m,1H), 7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H), 7.64-7.69(m, 2H), 7.84-7.86(m, 1H), 7.92(td, 1H) 323 (I) (DMSO-D6) δ 1.64-1.78(m,2H), 1.99-2.09(m, 2H), 2.17-2.29(m, 3H), 2.70-2.85(m, 1H), 3.04-3.19(m,3H), 3.28-3.38(m, 3H), 3.31 (s, 3H), 3.46-3.55(m, 2H), 3.66(t, 2H),4.12(t, 2H), 4.56-4.68(m, 1H), 4.81-4.86(m, 1H), 6.94-6.97(m, 2H),7.04(dd, 1H), 7.05(ddd, 1H), 7.34-7.39(m, 2H), 7.55(t, 1H) 324 (I)(CDCl₃) δ 1.45(s, 9H), 1.48-1.67(m, 4H), 1.75-1.85(m, 2H), 1.90-2.03 (m,3H), 2.42-2.51(m, 2H), 2.56(m, 1H), 2.71-2.84(m, 3H), 2.91-3.06(m, 1H),3.54(q, 2H), 3.75-3.88(m, 1H), 4.03(t, 2H), 4.27 (septet, 1H),4.68-4.82(m, 1H), 4.93-5.01(m, 1H), 6.75(dd, 1H), 6.90-7.00 (m, 3H),7.25-7.32(m, 3H) 325 (I) (DMSO-D6) δ 1.70-1.84(m, 2H), 2.00-2.09(m, 2H),2.20-2.29(m, 3H), 2.81-2.91(m, 1H), 3.09-3.21(m, 3H), 3.28-3.38(m, 3H),3.48-3.57 (m, 2H), 3.61-3.70(m, 1H), 4.61-4.72(m, 1H), 4.82-4.86(m, 1H),7.05(ddd, 1H), 7.14-7.27(m, 1H), 7.37(dd, 1H), 7.56(t, 1H), 7.76-7.79(m, 1H), 8.51(s, 1H), 8.80(d, 1H) 326 (I) (DMSO-D6) δ 1.70-1.78(m, 2H),2.00-2.09(m, 2H), 2.18-2.26(m, 2H), 3.05-3.17(m, 2H), 3.24-3.40(m, 2H),3.97-4.06(m, 2H), 4.44-4.52 (m, 2H), 4.59-4.70(m, 2H), 4.73(s, 2H),4.81-4.86(m, 1H), 4.91-4.93 (m, 2H), 6.90-6.93(m, 1H), 6.96-7.04(m, 1H),7.07-7.11(m, 1H), 7.17-7.20(m, 1H), 7.34-7.43(m, 2H), 7.52-7.55(m, 1H)327 (I) (CDCl₃) δ 1.52-1.63(m, 4H), 1.77-1.86(m, 2H), 1.92-2.03(m, 4H),2.44-2.50(m, 2H), 2.58-2.67(m, 1H), 2.77-2.83(m, 2H), 3.05(bs, 1H),3.36(s, 3H), 4.26-4.31(m, 2H), 6.74-6.77(m, 1H), 6.99-7.01 (m, 1H),7.30-7.33(m, 1H), 7.47(s, 1H) 328 (I) (CDCl₃) δ 1.43-1.67(m, 4H),1.73-1.91(m, 4H), 1.95-2.02(m, 2H), 2.42-2.50(m, 2H), 2.52-2.62(m, 1H),2.77-2..85(m, 2H), 2.92(bs, 2H), 3.06(s, 3H), 4.23-4.30(m, 1H), 5.26(s,2H), 6.73-6.79(m, 2H), 6.99-7.00(m, 1H), 7.29-7.32(m, 1H), 7.47-7.50(m,1H), 7.82-7.82 (m, 1H) 329 (I) (CDCl₃) δ 1.50-1.69(m, 4H), 1.77-1.86(m,2H), 1.92-2.02(m, 4H), 2.45-2.49(m, 2H), 2.59-2.65(m, 1H), 2.79-2.83(m,2H), 3.02(bs, 1H), 3.39(s, 3H), 4.26-4.30(m, 2H), 5.88(bs, 1H),6.74-6.77(m, 1H), 6.99-7.00(m, 1H), 7.30-7.32(m, 1H), 7.46(bs, 1H),7.65(s, 1H) 330 (I) (DMSO-D6) δ 1.73-3.63(m, 17H), 4.57-4.70(m, 1H),7.01-7.88(m, 7H) 331 (I) (DMSO-D6) δ 1.21(d, 6H), 1.37-2.03(m, 8H),2.33-3.42(m, 7H), 4.15-4.19(m, 1H), 4.37-4.45(m, 1H), 5.89(s, 2H),6.96-8.34(m, 4H) 332 (I) (DMSO-D6) δ 1.41-1.94(m, 8H), 2.37-2.78(m, 8H),3.32(s, 3H), 4.38-4.46(m, 1H), 6.96-7.78(m, 5H) 333 (I) (CDCl₃) δ1.80-1.96(m, 5H), 2.38(s, 4H), 2.41-3.00(m, 12H), 3.57-3.60 (m, 1H),4.26(s, 1H), 4.73-4.76(m, 1H), 6.73-7.32(m, 3H) 334 (I) (DMSO-D6) δ1.33-1.93(m, 8H), 2.33-3.27(m, 7H), 4.39-4.45(m, 1H), 4.49-4.53(m, 1H),6.96-8.98(m, 5H) 335 (I) (CDCl₃) δ 1.16-1.30(m, 1H), 1.33-1.48(m, 1H),1.76-2.75(m, 12H), 2.96-3.05(m, 1H), 3.72(s, 2H), 3.89-3.93(m, 1H),4.21-4.30 (m, 1H), 4.66-4.71(m, 1H), 6.72-7.32(m, 7H) 336 (I) (DMSO-D6)δ 1.37-2.83(m, 17H), 4.38-4.47(m, 1H), 5.76(s, 1H), 6.96-7.96(m, 6H) 337(I) (DMSO-D6) δ 1.33-1.99(m, 8H), 2.36-2.60(m, 4H), 2.73-2.82(m, 2H),2.94(s, 3H), 2.98-3.09(m, 1H), 3.55-3.66(m, 1H), 4.38-4.46 (m, 1H),4.56(s, 2H), 6.96-7.00(m, 1H), 7.23-7.27(m, 1H), 7.41-7.52 (m, 5H) 338(I) (DMSO-D6) δ 1.35-1.99(m, 8H), 2.37-2.46(m, 2H), 2.55-2.63(m, 2H),2.73-2.85(m, 2H), 2.92(s, 3H), 2.97-3.06(m, 1H), 3.55-3.65 (m, 1H),4.41-4.49(m, 1H), 4.56(s, 2H), 6.96-7.01(m, 1H), 7.25-7.27 (m, 1H),7.39-7.52(m, 5H)  1 (III) δ(DMSO-D6) 1.57-1.36(2H, m), 2.25-1.87(5H, m),2.45-2.33(2H, m), 3.16-2.97(2H, m), 3.37-3.17(4H, m), 3.45-3.40(1H, m),4.12 (0H, t), 4.53(1H, d), 4.67-4.58(1H, m), 4.84-4.77(1H, m), 5.45(1H,d), 7.03(1H, ddd), 7.19(2H, t), 7.42-7.33(3H, m), 7.55(1H, m),10.59-10.38 (1H, m)  2 (III) δ(DMSO-D6) 1.60-1.36(2H, m), 2.27-1.93(5H,m), 2.61-2.57(1H, m), 2.90-2.73(1H, m), 3.13-2.94(2H, m), 3.41-3.23(3H,m), 4.17-3.85 (2H, m), 4.68-4.47(2H, m), 4.84-4.77(1H, m), 5.43(1H, d),7.09-6.99 (1H, m), 7.40-7.27(6H, m), 7.55(1H, t), 11.13-10.92(1H, m)  3(III) δ(DMSO-D6) 1.27-1.07(1H, m), 1.57-1.36(1H, m), 2.24-1.89(5H, m),2.66-2.56(1H, m), 2.93-2.79(1H, m), 3.16-3.00(2H, m), 3.51-3.39 (2H, m),4.18(1H, t), 4.67-4.46(2H, m), 4.84-4.78(1H, m), 5.51-5.43 (1H, m),6.05(1H, s), 7.04(1H, dd), 7.24-7.17(1H, m), 7.48-7.33 (3H, m), 7.55(1H,dd), 10.41-10.23(1H, m)

TABLE VII Compound MP (Table) MS (° C.) ¹H NMR Can be prepared using:  3(IV) 495 181-182 (DMSO-D6) δ 1.2-2.8(bm, 14H), 3.1(bm, 1H), 3.35(s, 3H),3.5(bm, Example 12 (M + H) 1H), 4.4(m, 1H), 4.5(bm, 1H), 6.82(dd, 1H),7.1(dd, 1H), 7.4(t, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)  2 (IV) 495111-112 (DMSO-D6) δ 1.6-2.3(bm, 8H), 3.0-3.6(bm, 8H), 3.3(s, 3H),4.5-4.8 Example 12 and final product (M + H) (m, 2H), 6.9-7.1(m, 1H),7.2-7.4(m, 2H), 7.8(m, 2H), 7.94(d, 1H), isolated as Hydrochloride by8.03(d, 1H), 10.9(bm, 1H) treatment with a solution of HCl in dioxan andevaporation.  7 (IV) 459 149-150 (DMSO-D6) δ 1.2-3.7(bm, 16H), 3.75(s,3H), 3.85(bm, 1H), 4.6(bm, As for 2 (IV) above (M + H) 1H), 5.05(bm,1H), 6.9(m, 4H), 7.78(m, 2H), 7.92(d, 1H), 8.05(m, 1H), 11.0 and11.8(bm, 1H)  8 (IV) 463 126-127 (DMSO-D6) δ 1.2-3.6(bm, 16H), 3.9(bm,1H), 4.6 bm, 1H), 5.14 As for 2 (IV) above (M + H) (bm, 1H), 7.0(d, 2H),7.38(d, 2H), 7.75(m, 2H), 7.9(m, 1H), 8.05(m, 1H), 11.3 and 11.95(bm,1H)  9 (IV) 497 78-80 (DMSO-D6) δ 1.2-4.0(bm, 17H), 4.6(bm, 1H), 5.2(bm,1H), 7.0(dd, As for 2 (IV) above (M + H) 1H), 7.3(m, 1H), 7.58(d, 1H),7.78(d, 2H), 7.95(d, 1H), 8.05(m, 1H) 11.0 and 11.65(bm, 1H)  10 (IV)454 78-80 (DMSO-D6) δ 1.2-3.6(m, 17H), 4.25(bm, 1H), 4.98(m, 1H),7.03(d, Example 12 (M + H) 2H), 7.72(m, 4H), 7.9(s, 1H), 8.0(m, 1H)  11(IV) 465 82-83 (DMSO-D6) 1.2-3.4(m, 16H), 3.5(bm, 1H), 4.3(bm, 1H),4.85(m, Example 12 (M + H) 1H), 6.7(m, 1H), 7.0(m, 1H), 7.3(q, 1H),7.7(m, 2H), 7.9(s, 1H), 8.0 (m, 1H)  12 (IV) 447 64-65 (DMSO-D6) δ1.2-3.3(m, 16H), 3.45(bm, 1H), 4.25(m, 1H), 4.8(m, Example 12 (M + H)1H), 6.9(m, 2H), 7.1(t, 2H), 7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H)  13(IV) 500 110-111 (DMSO-D6) δ 1.2-4.8(bm, 24H), 6.95(dd, 2H), 7.5(m, 2H),7.8(m, As for 2 (IV) above (M + H) 2H), 7.95(s, 1H), 8.02(d. 1H),9.85(d, 1H), 10.7(bm, 1H)  14 (IV) 457 140-142 (DMSO-D6) δ 1.2-4.8(m,24H), 6.86(bm, 2H), 7.02(m, 2H), 7.75 Example 12 (M + H) (bm, 2H),7.90(s, 1H), 8.03(bm, 1H)  15 (IV) 491 94-95 (DMSO-D6) δ 1.2-4.8(bm, 24H). 6.8(bd, 1H), 7.0(bs, 1H), 7.3(d, Example 12 (M + H) 1H), 7.75(m,2H), 7.9(s, 1H), 8.0(m, 1H)  16 (IV) 477 150-152 (DMSO-D6) δ 1.2-4.6(bm,21H), 7.0(bm, 2H), 7.3(bm, 2H), 7.75 Example 12. (M + H) (m, 2H), 7.9(s,1H), 8.0(m, 1H)  17 (IV) 461 219-220 (DMSO-D6) δ 1.2-4.8(bm, 21 H),6.9-7.3(m, 4H), 7.75(m, 2H), 7.92 As for 2 (IV) above (M + H) (s, 1 h),8.02(m, 1H).  18 (IV) 511 104-105 (DMSO-D6) δ 1.2-5.0(bm, 21H), 7.3(d,1H) 7.4(dd, 1H), 7.6(dd, Example 12 and final product (M + H) 1H),7.75(m, 2H), 7.95(s, 1H), 8.0(d, 1H), 9.5 and 9.7(bs, 1H) isolated astrifluoroacetate by evaporation of Reverse Phase HPLC fractions.  19(IV) 495 76-77 (DMSO-D6) δ 1.2-5.0(bm, 21H), 7.2(m, 1H), 7.3(m, 1H),7.45(m, As for 18 (IV) above (M + H) 1H), 7.75(m, 2H), 7.95(s, 1H),8.05(m, 1H), 9.5(bm, 1H)  20 (IV) 479 230-232 (DMSO-D6) δ 1.2-3.7(bm,19H), 4.4-4.7(bm, 2H), 7.02(t, 1H), 7.3 As for 2 (IV) above (M + H) (m,2H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)  21 (IV) 495 69-70 (DMSO-D6)1.2-4.0(m, 19 H), 4.4-4.8(m, 2H), 7.3(m, 2H), 7.5(m, As for 18 (IV)above (M + H) 1H), 7.75(m, 2H), 7.98(s, 1H), 8.0(m, 1H), 9.5(bm, 1H)  22(IV) 475 130-132 (CDCl₃) δ 1.0-3.6(m, 19H), 3.7(s, 3H), 4.6(m, 2H),6.6-6.9(m, 3H), As for 2 (IV) above (M + H) 7.7(m, 2H), 8.0(m, 2H)  24(IV) 462 72-73 (DMSO-D6) 1.6(m, 2H), 1.8(m, 1H), 2.01(m, 4H), 2.3(m,1H), 2.55 Example 13 (M + H) (m, 2H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m,1H), 3.58(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.7(d,1H), 6.8-7.0(m, 3H), 7.2 (m, 1H), 7.5(m, 1H), 9.5(bs, 1H)  26 (IV) 458111-112 (DMSO-D6) δ 1.4-3.6(m, 17H), 3.8(2s, 6H), 4.2-4.5(m, 3H), 6.7(m,Example 13 (M + H) 2H), 6.82(m, 2H), 6.9-7.2(m, 2H)  27 (IV) 440 73-75(DMSO-D6) δ 1.6-1.9(m, 3H), 2.0-2.3(m, 5H), 2.4-2.6(m, 2H), 2.9 Example13 (M + H) (m, 2H), 3.18(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.7(s, 3H),3.8(s, 3H), 4.2(bs, 2H), 4.4 and 4.6 (2m, 1H), 6.7(d, 1H), 6.9(m, 5H),7.0 (d, 1H), 9.7(bm, 1H)  28 (IV) 462 81-83 (DMSO-D6) δ 1.6(m, 2H),1.8(m, 1H), 2.05(m, 4H), 2.3(m, 1H), 2.5 Example 13 (M + H) (m, 1H),2.9(m, 2H), 3.2(m, 2H), 3.3(m, 2H), 3.4(m, 1H), 3.55(m, 2H), 3.8(s, 3H),4.3(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H), 6.81 (d, 1H), 6.9(s, 1H),7.05(m, 1H), 7.35(m, 2H), 9.76(bm, 1H)  29 (IV) 424 97-99 (DMSO-D6) δ1.4-2.6(m, 14H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), Example 13 (M + H)3.55(m, 2H), 3.8(s, 3H), 4.3(bs, 2H), 4.5 and 4.7(m, 1H), 6.65(d, 1H),6.9(m, 4H), 7.1(m, 1H), 9.5(bs, 1H)  30 (IV) 458 78-79 (DMSO-D6) δ1.5-2.6(m, 13H), 2.3(s, 3H), 2.9(m, 2H), 3.2(m, 2H), Example 13 (M + H)3.4(m, 1H), 3.55(m, 2H), 4.3(bs, 2H), 4.55 and 4.75(m, 1H), 6.67 (d,1H), 6.85(m, 3H), 7.0(dd, 1H), 7.32(t, 1H), 9.5(bs, 1H)  31 (IV) 444100-101 (DMSO-D6) δ 1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), 2.5Example 13 (M + H) (m, 2H), 2.9(m, 2H), 3.18(m, 2H), 3.4(m, 1H), 3.5(m,2H), 3.8(s, 3H), 4.2(bs, 2H), 4.6 and 4.8(m, 1H), 6.62(d, 1H), 6.8(m,2H), 7.0 (m, 2H), 7.36(m, 2H), 9.7(bs, 1H)  32 (IV) 428 74-75 (DMSO-D6)1.6(m, 2H), 1.8(m, 1H), 2.0(m, 4H), 2.3(m, 1H), 2.5 Example 13 (M + H)(m, 2H), 2.9(m, 2H), 3.2(m, 2H), 3.4(m, 1H), 3.5(m, 2H), 3.8(s, 3H),4.2(bs, 2H), 4.5 and 4.7(m, 1H), 6.7(d, 1H), 6.85(d, 1H), 6.9(s, 1H),7.02(m, 1H), 7.04(m, 1H), 7.18(m, 2H), 9.6(m, 1H)  33 (IV) 478 117-119(DMSO-D6) δ 1.6-3.6(m, 17H), 3.8(s, 3H), 4.25(bs, 2H), 4.6 and 4.9Example 13 (M + H) (m, 1H), 6.6(d, 1H), 6.8(m, 2H), 7.3(m, 1H), 7.4(m,1H), 7.6(m, 1H), 9.5(bs, 1H)  34 (IV) 462 109-110 (DMSO-D6) δ 1.6-3.6(m,17H), 3.8(s, 3H), 4.25(bs, 2H), 4.55 and Example 13 (M + H) 4.85(m, 1H),6.6(d, 1H), 6.8(m, 2H), 7.2(m, 1H), 7.3(m, 1H), 7.45 (m, 1H), 9.5(bs,1H)  37 (IV) 442 89-90 (DMSO-D6) δ 1.6-3.6(m, 20H), 3.8(s, 3H), 4.25(bs,2H), 4.45 and Example 13 (M + H) 4.75(m, 1H), 6.6(d, 1H), 6.8(m, 2H),7.0(m, 3H), 9.6(bs, 1H)  38 (IV) 471 143-145 (DMSO-D6) δ 1.6-3.6(m,19H), 4.2-4.8(m, 2H), 7.0(m, 1H), 7.2(d, As for 18 (IV) above (M + H)1H), 7.22(s, 1H), 7.8(d, 1H), 8.5(d, 1H), 8.8(s, 1H)  39 (IV) 475141-142 (DMSO-D6) δ 1.6-3.6(m, 16H), 4.2-4.8(m, 2H), 6.9(m, 1H), 7.2(m,As for 18 (IV) above (M + H) 1H), 7.5(m, 1H), 7.8(d, 1H), 8.5(d, 1H),8.8(d, 1H)  41 (IV) 471 160-162 (DMSO-D6) δ 1.6-3.6(m, 16H), 3.8(s, 3H),4.2-4.8(m, 2H), 6.7(m, As for 18 (IV) above (M + H) 1H), 6.9-7.2(m, 2H),7.8(d, 1H), 8.5(d, 1H), 8.8(d, 1H)  42 (IV) 453 116-118 (DMSO-D6) δ1.6-3.6(m, 16H), 3.7(s, 3H), 4.2-4.8(m, 2H), 6.8-7.1 As for 18 (IV)above (M + H) (m, 3H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H) 43 (IV) 475 109-110 (DMSO-D6) δ 1.6-3.6(m, 16H), 4.2-4.8(m, 2H),7.07(m, 1H), 7.35 As for 18 (IV) above (M + H) (m, 2H), 7.82(d, 1H),8.52(d, 1H), 8.8(d, 1H), 9.6(bs, 1H)  44 (IV) 437 136-137 (DMSO-D6) δ1.6-3.2(m, 15H), 3.3(s, 3H), 3.6(m, 1H), 4.22(m, Example 12 (M + H) 1H),4.5(m, 1H), 6.8(d, 2H), 7.10(d, 2H), 7.82(d, 1H), 8.52(d, 1H), 8.8(d,1H)  89 (IV) 471 100-102 (DMSO-D6) δ 1.0-4.2(m, 21H), 6.0(m, 1H),6.18(m, 1H), 6.42(m, As for 18 (IV) above (M + H) 1H), 7.02(d, 1H),7.6(d, 1H), 7.85(d, 1H)  47 (IV) 441 133-136 (DMSO-D6) δ 1.6-4.8(m,18H), 6.9-7.2(m, 4H), 7.82(d, 1H), 8.52(d, As for 18 (IV) above (M + H)1H), 8.8(d, 1H)  48 (IV) 491 105-106 (DMSO-D6) δ 1.6-4.8(m, 18H), 6.3(d,1H), 6.4(d, 1H), 6.58(s, 1H), As for 18 (IV) above (M + H) 6.9(d, 1H),7.52(d, 1H), 7.8(d, 1H)  49 (IV) 475 123-125 (DMSO-D6) δ 1.6-4.8(m,18H), 7.2(m, 1H), 7.3(m, 1H), 7.45(m, As for 18 (IV) above (M + H) 1H),7.82(d, 1H), 8.52(d, 1H), 8.8(d, 1H)  50 (IV) 459 93-94 (DMSO-D6) δ1.6-4.8(m, 18H), 7.05(m, 1H), 7.3(m, 2H), 7.82(d, As for 18 (IV) above(M + H) 1H), 8.52(d, 1H), 8.8(d, 1H), 9.7(bm, 1H) 271 (IV) 507 102-103(DMSO-D6) δ 1.6-3.8(m, 16H), 3.3(s, 3H), 3.8(d, 3H), 4.4-4.7(m, Example12 (M + H) 2H), 6.95(m, 1H), 7.1(m, 2H), 7.78(m, 2H), 7.95(s, 1H),8.03(d, 1H) 272 (IV) 505 97-98 (DMSO-D6) δ 1.6-4.8(m, 27H), 7.1(s, 2H),7.6(m, 2H), 7.95(s, 1H), As for 18 (IV) above (M + H) 8.03(d, 1H) 273(IV) 511 110-112 (DMSO-D6) δ 1.4-3.8(m, 16H), 3.3(s, 3H), 4.4-5.0(m,2H), 7.22(m, As for 18 (IV) above (M + H) 2H), 7.3(m, 1H), 7.75(m, 2H),7.95(s, 1H), 8.02(d, 1H) 274 (IV) 511 114-115 (DMSO-D6) δ 1.4-3.8(m,16H), 3.3(s, 3H), 4.4-5.0(m, 2H), 7.02(m, Example 12 (M + H) 1H), 7.4(m,2H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H) 275 (IV) 491 88-89 (DMSO-D6)δ 1.4-3.8(m, 16H), 2.25(s, 3H), 3.3(s, 3H), 4.2-4.8(m, Example 12 (M +H) 2H), 7.02(m, 2H), 7.22(m, 1H), 7.75(m, 2H), 7.95(s, 1H), 8.02(d, 1H)276 (IV) 491 182-183 (DMSO-D6) δ 1.4-3.8(m, 16H), 2.25(s, 3H), 3.3(s,3H), 4.4-4.6(m, Example 12 (M + H) 2H), 6.74(d, 1H), 7.02(s, 1H),7.22(d, 1H), 7.75(m, 2H), 7.90(s, 1H), 8.0(d, 1H) 277 (IV) 499 162-164(DMSO-D6) δ 1.6-3.8(m, 19H), 2.25(s, 3H), 3.3(s, 3H), 4.5-5.0(m, As for2 (IV) above (M + H) 2H), 7.14(t, 1H), 7.8(m, 4H), 7.95(m, 1H), 8.02(d,1H), 10.9(bm, 1H) 278 (IV) 528 120-122 (DMSO-D6) δ 1.5-5.0(m, 29H),6.9-7.2(m, 4H), 7.75(m, 2H), 7.95 As for 2 (IV) above (M + H) (s, 1H),8.02(d, 1H), 10.2(bs, 1H), 11.0-11.3(bm, 1H) 279 (IV) 505 97-99(DMSO-D6) δ 1.18(t, 3H), 1.6-3.7(m, 17H), 2.62(q, 2H), 3.3(s, 3H),Example 12 (M + H) 4.4-4.8(m, 1H), 6.8-7.1(m, 2H), 7.3(m, 1H), 7.75(m,2H), 7.95(s, 1H), 8.02(m, 1H), 9.4(bs, 1H) 280 (IV) 494 138-140(DMSO-D6) δ 1.8(m, 2H), 2.1-4.4(m, 14H), 3.3(s, 3H), 4.62(bm, As for 2(IV) above (M + H) 1H), 4.9 and 5.1(m, 1H), 7.65(m, 1H), 7.8(m, 2H),7.85(m, 2H), 7.95 (d, 1H), 8.01(d, 1H), 8.3(t, 1H), 9.0(t, 1H), 9.15(t,1H), 10.35(bs, 1H), 11.5(bs, 1H) 281 (IV) 499 98-99 (DMSO-D6) δ 1.2(s,9H), 1.3-3.6(m, 20H), 4.5(m, 1H), 6.8(t, 1H), Example 12 (M + H) 6.9(d,1H), 7.1(t, 1H), 7.2(d, 1H), 7.7(m, 2H), 7.9(s, 1H), 8.0(d, 1H) 282 (IV)483 79-80 (DMSO-D6) δ 1.2-3.6(m, 22H), 3.3(s, 3H), 4.22 and 4.5(m, 2H),Example 12 (M + H) 6.67(d, 1H), 6.8(s, 1H), 7.08(d, 1H), 7.75(m, 2H),7.9(s, 1H), 8.0(d, 1H) 283 (IV) 559 113-115 (DMSO-D6) δ 1-1.48(m, 29H),3.3(s, 3H), 7.0(m, 1H), 7.18(m, 2H), Example 12 (M + H) 7.75(m, 2H),7.9(s, 1H), 8.0(m, 1H) 284 (IV) 520 111-112 (DMSO-D6) δ 1.6-4.0(m, 19H),4.6 and 4.9(m, 2H), 7.2(m, 1H), 7.4-7.8 As for 18 (IV) above (M + H) (m,6H), 7.95(s, 1H), 8.02(d, 1H), 9.5(bm, 1H) 285 (IV) 544 111-112(DMSO-D6) δ 1.6-3.2(m, 15H), 3.3(s, 3H), 3.5(m, 1H), 4.5 and 4.6 Example12 (M + H) (m, 2H), 6.9(d, 1H), 7.35(d, 1H), 7.5(dd, 1H), 7.75(m, 2H),7.81(d, 1H), 7.9(s, 1H), 8.0(dd, 1H), 8.68(d, 1H) 286 (IV) 491 115-117(DMSO-D6) δ 1.6-3.2(m, 16H), 3.3(s, 3H), 3.35-3.6(m, 3H), 4.4-4.9Example 12 (M + H) (m, 2H), 6.9(m, 1H), 7.0-7.2(m, 2H), 7.75(m, 2H),7.92(s, 1H), 8.02(m, 1H) 287 (IV) 443 142-144 (DMSO-D6) δ 1.6-3.4(m,14H), 3.3(s, 3H), 3.4-3.7(m, 2H), 4.6-4.8 Example 12 (M + H) (m, 2H),7.0(m, 3H), 7.3(m, 2H), 7.75(m, 2H), 7.92(s, 1H), 8.04(dd, 1H) 288 (IV)525 84-86 (DMSO-D6) δ 1.6-3.4(m, 22H), 4.2-4.7(m, 2H), 7.38(d, 1H),7.5(d, As for 18 (IV) above (M + H) 1H), 7.75(m, 2H), 7.95(s, 1H),8.02(m, 1H) 289 (IV) 491 149-151 (DMSO-D6) δ 1.3-2.0(m, 8H), 2.22(s,3H), 2.3-2.6(m, 4H), 2.8(m, Example 12 (M + H) 2H), 3.1(m, 1H), 3.3(s,3H), 3.5(m, 1H), 4.3-4.6(m, 2H), 6.84(dd, 1H), 7.0(d, 1H), 7.2(m, 1H),7.75(m, 2H), 7.9(s, 1H), 8.0(dd, 1H) 290 (IV) 502 93-95 (DMSO-D6) δ1.6-4.0(m, 16H), 3.3(s, 3H), 4.4-5.1(m, 2H), 7.4(t, As for 18 (IV) above(M + H) 1H), 7.8(m, 3H), 7.9-8.1(m, 3H), 9.5-10.0(bm, 1H) 293 (IV) 44566-68 (DMSO-D6) δ 1.6-3.0(m, 7H), 2.8(m, 1H), 3.2(m, 3H), 3.3(s, 3H),Example 15 (M + H) 3.4-3.7(m, 4H), 4.62(m, 1H), 5.1-5.4(m, 2H), 7.2(m,1H), 7.8(m, 2H), 7.95(m, 1H), 8.02(d, 1H), 8.6(m, 2H), 9.5(bs, 1H) 339(I) (M + H) foam (DMSO-D6) δ 1.42-1.70(m, 5H), 1.84-1.94(m, 3H),2.35-2.42 Example 2 step c 458 (m, 2H), 2.54-2.62(m, 1H), 2.73-2.87(m,3H), 3.02-3.10(m, 1H), 3.30-3.36(m, 1H), 4.39-4.44(m, 1H), 4.53-4.57(m,1H), 6.95-6.99 (m, 1H), 7.24-7.25(m, 1H), 7.47-7.50(m, 1H), 7.56-7.67(m,2H), 7.77-7.82(m, 1H), 7.94-7.96(m, 1H) 340 (I) (M + H) 156-157(DMSO-D6) δ 1.40-1.99(m, 8H), 2.35-2.46(m, 2H), 2.54-2.62 Example 2 stepc 484 (m, 1H), 2.73-2.85(m, 3H), 3.02-3.13(m, 1H), 3.60-3.72(m, 1H),4.39-4.47(m, 1H), 4.51-4.64(m, 1H), 6.96-7.00(m, 1H), 7.25-7.26 (m, 1H),7.50(d, 1H), 7.59-7.63(m, 1H), 7.74-7.78(m, 1H), 8.06-8.09(m, 2H),8.45-8.48(m, 1H), 8.96-8.98(m, 1H) 341 (I) (M + H) 127-129 (DMSO-D6) δ1.44-1.99(m, 8H), 2.40-2.48(m, 2H), 2.58-2.67 Example 2 step c usingQuinoxaline- 485 (m, 1H), 2.75-2.90(m, 3H), 3.04-3.16(m, 1H),3.56-3.69(m, 1H), 6-carboxylic acid (obtained from 4.40-4.49(m, 1H),4.53-4.63(m, 1H), 6.96-7.00(m, 1H), 7.26-7.27 hydrolysis of thecommercially (m, 1H), 7.48-7.51(m, 1H), 7.85-7.88(m, 1H), 8.09-8.11(m,available Quinoxaline-6-carboxylic 1H), 8.16-8.19(m, 1H), 9.01(s, 2H)acid methyl ester) 342 (I) (M + H) foam (DMSO-D6) δ 1.36-1.44(2H, m),1.55-1.61(2H, m), 1.76-1.82 Example 2 step using 3-Amino-4- 532 (2H, m),1.89-1.96(2H, m), 2.34-2.41(3H, m), 2.72-2.80(2H, m),methanesulfonyl-thiophene-2- 2.95(2H, t), 3.21(3H, s), 4.15-4.22(2H, m),4.38-4.46(1H, m), 5.87 carboxylic acid (obtained from (2H, s),6.96-6.99(2H, m), 7.24-7.26(2H, m), 7.49(1H, d), 8.34 hydrolysis of thecommercially (1H, s) available 3-Amino-4- methanesulfonyl-thiophene-2-carboxylic acid methyl ester)  63 (IV) 491 127-129 (DMSO-D6) δ1.42-1.96(8H, m), 2.26(3H, s), 2.32-2.41(2H, m), Example 2 step c (M +H) 2.53-2.59(2H, m), 2.67-3.11(4H, m), 3.24(3H, s), 4.28-4.35(2H, m),6.77-6.81(1H, m), 6.95(1H, d), 7.26(1H, dd), 7.50(1H, ddd), 7.70(1H, d),7.76-7.82(1H, m), 7.98(1H, ddd)  79 (IV) 497 168-169 (DMSO-D6) δ1.41-1.49(2H, m), 1.53-1.60(2H, m), 1.80(2H, d), Example 2 step c (M +H) 1.92(2H, dz), 2.27(3H, s), 2.38(2H, t), 2.54-2.62(2H, m), 2.77(2H,t), 2.93-3.12(2H, m), 3.40(3H, s), 4.33(2H, dt), 6.80(1H, dd), 6.95 (1H,d), 7.26(1H, d), 7.49(1H, d), 7.77(1H, d) 423 (I) (M + H) 181-183(DMSO-D⁶) δ 1.44-1.63(6H, m), 1.91-1.98(3H, m), 2.36-2.39 Example 2 stepc 499 (2H, m), 2.53-2.62(4H, m), 2.76-2.90(2H, m), 3.03-3.11(1H, m),3.34-3.42(1H, m), 4.40-4.45(1H, m), 4.56-4.64(1H, m), 6.96-6.99 (1H, m),7.24(1H, s), 7.48-7.51(1H, m), 7.61-7.65(1H, m), 8.39-8.47(2H, m),9.06-9.08(1H, m) 578 (I) (M + H) 145-147 (DMSO-D⁶) δ 1.33-1.45(2H, m),1.53-1.64(2H, m), 1.76-1.94 Example 2 step c 473 (4H, m), 2.36-2.44(2H,m), 2.55-2.64(1H, m), 2.70-2.80(3H, m), 3.03-3.15(1H, m), 4.35-4.44(1H,m), 4.51-4.61(1H, m), 5.08-5.20 (1H, m), 6.93-7.00(2H, m), 7.25-7.34(2H,m), 7.45-7.50 (1H, m), 7.57-7.63(1H, m), 8.33(1H, s), 8.50-8.62(1H, m)580 (I) (M + H) >200 (DMSO-D⁶) δ 1.43-1.65(4H, m), 1.85-1.96(3H, m),2.32-2.41 Example 2 step c 500 (2H, m), 2.54-2.62(2H, m), 2.73-3.14(4H,m), 3.40-3.47(1H, m), 4.37-4.45(1H, m), 4.53-4.62(1H, m), 6.45(1H, d),6.93-7.00(1H, m), 7.17-7.26(2H, m), 7.33-7.59(4H, m), 11.99(1H, s) 419(I) (M + H) >200 (DMSO-D⁶) δ 1.25-1.68(5H, m), 1.72-1.81(2H, m),1.88-1.95 Example 2 step c 464 (2H, m), 2.22(3H, s), 2.31-2.40(2H, m),2.60-2.78(3H, m), 2.92-3.00 (1H, m), 3.44-3.52(1H, m), 4.36-4.49(2H, m),5.92-6.11(1H, m), 6.91-7.06(1H, m), 7.25(1H, s), 7.30-7.41(1H, m),7.44-7.54 (1H, m), 11.86(1H, s) 550 (I) (M + H) 80-85 (DMSO-D⁶) δ1.40-1.65(5H, m), 1.83-1.96(3H, m), 2.31-2.43 Example 2 step c 484 (2H,m), 2.50-2.56(1H, m), 2.69-2.92(4H, m), 3.08-3.17(1H, m), 4.36-4.42(1H,m), 4.65-4.73(1H, m), 6.94-7.00(1H, m), 7.19-7.25 (1H, m), 7.45-7.50(1H,m), 7.58-7.71(3H, m), 8.00-8.05 (1H, m), 8.39-8.46(1H, m), 8.91-8.96(1H,m) 426 (I) (M + H) 158-159 (DMSO-D6) δ 1.36-1.45(2H, m), 1.53-1.61(2H,m), 1.72-1.79 Example 2 step c 464 (2H, m), 1.88-1.96(2H, m),2.35-2.43(2H, m), 2.52-2.57(1H, m), 2.72-2.79(2H, m), 2.85-2.94(2H, m),3.32-3.38(1H, m), 3.49 (3H, s), 3.99-4.12(1H, m), 4.34-4.51(1H, m),6.36(1H, d), 6.90-7.06 (1H, m), 7.21-7.29(1H, m), 7.42-7.54(2H, m),7.91-8.03(1H, m) 416 (I) (M + H) 133-135 (DMSO-D6) δ 1.38-1.45(2H, m),1.53-1.60(2H, m), 1.66-1.84 Example 2 step c 448 (2H, m), 1.88-1.95(2H,m), 2.34-2.41(2H, m), 2.51-2.58(1H, m), 2.73-2.78(3H, m), 3.01-3.10(1H,m), 3.29-3.36(3H, m), 3.53-3.63 (1H, m), 4.38-4.53(2H, m), 6.94-7.01(1H,m), 7.21-7.28 (1H, m), 7.29-7.35(1H, m), 7.47-7.52(1H, m), 7.68-7.75(1H,m), 8.42-8.50(1H, m) 575 (I) (M + H) 140-142 Example 2 step c 645 534(I) (M + H) 189-190 Example 2 step c 543 294 (IV) (M + H) foam (CDCl₃) δ1.32-1.45(1H, m), 1.56-1.71(2H, m), 1.79-2.01(5H, Example 2 step c 529m), 2.46-2.61(3H, m), 2.79-2.87(3H, m), 2.92-3.16(4H, m), 3.36-3.42 (1H,m), 4.28-4.33(1H, m), 4.79(1H, t), 6.90(2H, dd), 7.12 (1H, dt), 7.49(1H,dd), 7.89(1H, ddd), 8.01(1H, dd)  67 (IV) (M + H) 132-133 (CDCl₃) δ1.38-1.65(2H, m), 1.73-2.04(6H, m), 2.40-2.67(3H, Example 2 step c 495m), 2.72-2.89(3H, m), 2.99-3.08(1H, m), 3.23-3.28(3H, m), 3.33-3.53 (1H,m), 4.21-4.33(1H, m), 4.61-4.86(1H, m), 6.87-6.92(2H, m), 7.10-7.14(1H,m), 7.31-7.37(1H, m), 7.55-7.70(2H, m), 8.07 (1H, td)  83 (IV) (M + H)foam (CDCl₃) δ 1.50-1.63(2H, m), 1.85-2.00(6H, m), 2.44-2.51(2H, Example2 step c 501 m), 2.56-2.66(1H, m), 2.80-2.88(2H, m), 3.01(2H, s),3.20(3H, s), 4.27-4.51(3H, m), 6.91(2H, dd), 7.13(1H, dt), 7.23(1H, d),7.63 (1H, d) 295 (IV) (M + H) (CDCl₃) δ 1.75-2.03(10H, m), 2.18-2.19(3H,m), 2.44-2.54(2H, Example 2 step c 491 m), 2.77-2.89(3H, m),3.00-3.09(1H, m), 3.23-3.28(3H, m), 3.36-3.52 (1H, m), 4.63-4.85(1H, m),6.70-6.75(1H, m), 7.05-7.11(2H, m), 7.31-7.37(1H, m), 7.56-7.68(2H, m),8.05-8.10(1H, m) 568 (I) (M + H) (DMSO-D6) δ 1.21-1.95(8H, m),2.35-2.42(2H, m), 2.57-2.66 Example 2 step c 558 (1H, m), 2.72-2.77(2H,m), 3.08-3.17(1H, m), 4.08-4.13(1H, m), 4.29(2H, d), 4.40-4.46(3H, m),6.96-7.00(1H, m), 7.25-7.26(1H, m), 7.48-7.51(1H, m), 7.58-7.62(1H, m),8.01-8.07(2H, m), 8.40-8.43 (1H, m), 8.75-8.78(2H, m) 296 (IV) (M + H)(CDCl₃) δ 1.58-1.68(4H, m), 1.85(2H, s), 2.00(2H, s), 2.19(3H, s),Example 2 step c 525 2.51-2.59(3H, m), 2.80-2.92(3H, m), 2.98-3.16(4H,m), 3.37-3.43 (1H, m), 4.33(1H, s), 4.76-4.85(1H, m), 6.72-6.74(1H, m),7.06-7.12(2H, m), 7.45-7.53(1H, m), 7.88-7.91(1H, m), 8.00-8.02 (1H, m)471 (I) 472 δ 1.40(m, 2H), 1.57(m, 2H), 1.79(m, 2H), 1.90(m, 2H),2.40(m, 2H), Example 2 step c (M + H) 2.58(m, 1H), 2.79(m, 2H), 2.87(m,2H), 4.30(d, 2H), 4.43(m, 1H), 6.97(dd, 1H), 7.13(m, 2H), 7.25(d, 1H),7.43(d, 1H), 7.49(d, 1H), 7.65(m, 2H) 475 (I) 526 (DMSO-D6) δ1.67-1.78(m, 2H), 1.95-2.09(m, 3H), 2.18-2.27 Example 2 step c (M + H)(m, 2H), 2.44(d 3H), 2.77-2.88(m, 1H), 3.08-3.19(m, 3H), 3.33-3.52 (m,5H), 3.59-3.67(m, 1H), 4.60-4.68(m, 1H), 4.84(s, 1H), 7.05(ddd, 1H),7.14-7.27(m, 1H), 7.37(dd, 1H), 7.55(t, 1H), 7.61 (q, 1H), 7.70-7.71(m,2H), 7.78-7.80(m, 1H), 7.86-7.89(m, 1H), 569 (I) 512 (DMSO-D6) δ1.65-1.80(m, 2H), 1.99-2.09(m, 2H), 2.19-2.30 Example 2 step c (M + H)(m, 3H), 2.77-2.90(m, 1H), 3.07-3.21(m, 3H), 3.30-3.37(m, 3H),3.47-3.57(m, 2H), 3.59-3.71(m, 1H), 4.59-4.69(m, 1H), 4.82-4.86 (m, 1H),7.05(ddd, 1H), 7.37(dd, 1H), 7.49(s, 2H), 7.55(t, 1H), 7.64-7.69(m, 2H),7.84-7.86(m, 1H), 7.92(td, 1H) 477 (I) 507 (DMSO-D6) δ 1.64-1.78(m, 2H),1.99-2.09(m, 2H), 2.17-2.29 Example 2 step c (M + H) (m, 3H),2.70-2.85(m, 1H), 3.04-3.19(m, 3H), 3.28-3.38(m, 3H), 3.31(s, 3H),3.46-3.55(m, 2H), 3.66(t, 2H), 4.12(t, 2H), 4.56-4.68 (m, 1H),4.81-4.86(m, 1H), 6.94-6.97(m, 2H), 7.04(dd, 1H), 7.05 (ddd, 1H),7.34-7.39(m, 2H), 7.55(t, 1H), 584 (I) 592 (CDCl₃) δ 1.45(s, 9H),1.48-1.67(m, 4H), 1.75-1.85(m, 2H), 1.90-2.03 Example 2 step c (M + H)(m, 3H), 2.42-2.51(m, 2H), 2.56(m, 1H), 2.71-2.84(m, 3H), 2.91-3.06(m,1H), 3.54(q, 2H), 3.75-3.88(m, 1H), 4.03(t, 2H), 4.27(septet, 1H),4.68-4.82(m, 1H), 4.93-5.01(m, 1H), 6.75(dd, 1H), 6.90-7.00(m, 3H),7.25-7.32(m, 3H) 325 (I) 491 (DMSO-D6) δ 1.69-1.83(2H, m), 1.98-2.11(3H,m), 2.17-2.28 Example 2 step c using acid prepared (M + H) (3H, m),2.81-2.92(1H, m), 3.08-3.21(3H, m), 3.47-3.59(2H, m), according toJournal of Heterocyclic 3.61-3.71(1H, m), 4.61-4.73(2H, m),4.82-4.86(1H, m), 7.05 chemistry, 1972, p1149 (1H, ddd), 7.37(1H, dd),7.56(1H, t), 7.77(1H, ddd), 8.51(1H, s), 8.80(1H, d) 585 (I) 507(DMSO-D6) δ 1.70-1.78(m, 2H), 2.00-2.09(m, 2H), 2.18-2.26 Example 2 stepc, using 3-tert- (M + H) (m, 2H), 3.05-3.17(m, 2H), 3.24-3.40(m, 2H),3.97-4.06(m, 2H), butoxycarbonylmethoxy-benzoic 4.44-4.52(m, 2H),4.59-4.70(m, 2H), 4.73(s, 2H), 4.81-4.86(m, acid, followed by theaddition of 1H), 4.91-4.93(m, 2H), 6.90-6.93(m, 1H), 6.96-7.04(m, 1H),(1M) HCl in ether to form final 7.07-7.11(m, 1H), 7.17-7.20(m, 1H),7.34-7.43(m, 2H), 7.52-7.55 compound as hydrochloride salt. (m, 1H),(HCl also cleaved tert-butyl ester to leave acid.) 586 (I) 492 (DMSO-D6)δ 1.56-1.87(3H, m), 1.94-2.17(5H, m), 3.06-3.27(7H, Prepared bydeprotection of 584(I) (M + H) m), 3.50-3.78(3H, m), 4.19(2H, t),4.57-4.69(1H, m), 4.80-4.85(1H, using trifluoroacetic acid in m),6.98-7.10(4H, m), 7.34-7.44(2H, m), 7.57(1H, dd) dichloromethane 588 (I)551 145 (CDCl₃) δ 0.09(2H, dd), 0.44(2H, dd), 0.83-0.89(1H, m),1.67-1.78 Example 2 step c (M + H) (2H, m), 1.96-2.09(3H, m),2.18-2.28(4H, m), 2.78-2.89(1H, m), 3.08-3.20(4H, m), 3.34(2H, s),3.47-3.65(3H, m), 4.59-4.68 (1H, m), 4.84(1H, s), 7.05(1H, ddd),7.36(1H, dd), 7.55(1H, t), 7.73-7.81 (2H, m), 7.90(1H, t), 8.00(1H, d) 71 (IV) 497 (CDCl₃) δ 1.56(2H, qd), 1.79-1.99(8H, m), 2.19(3H, s),2.45-2.52 Example 2 step c (M + H) (2H, m), 2.60(1H, tt), 2.76-2.83(2H,m), 2.91-3.11(2H, m), 3.21 (3H, s), 4.28-4.35(1H, m), 6.74(1H, d),7.05-7.12(2H, m), 7.24 (1H, d), 7.63(1H, d) 245 (IV) 486 120-126 (CDCl₃)δ 1.45-1.61(2H, m), 1.80-2.03(6H, m), 2.19(3H, s), 2.45-2.53 Example 2step c using 2-Oxo-2,3- (M + H) (2H, m), 2.54-2.62(1H, m), 2.79-3.09(4H,m), 3.80-3.99(1H, dihydro-benzothiazole-6-carboxylic m), 4.28-4.34(1H,m), 4.62-4.81(1H, m), 6.73(1H, d), 7.05-7.12 acid prepared according toChem. (3H, m), 7.30(1H, dd), 7.47(1H, d) Pharm. Bull. 1988, 36, p2253297 (IV) 526 115-117 (CDCl₃) δ 1.42-1.64(2H, m), 1.78-1.87(3H, m),1.93-2.01(3H, Example 2 step c (M + H) m), 2.19(3H, s), 2.44-2.51(2H,m), 2.57(1H, tt), 2.75-2.88(3H, m), 3.01-3.14(1H, m), 3.64-3.73(1H, m),4.27-4.33(1H, m), 4.65 -4.74 (1H, m), 6.73(1H, d), 7.07(1H, dd),7.11(1H, d), 7.52(1H, dd), 7.58(1H, d), 8.11(1H, d) 298 (IV) 480 120-126(CDCl₃) δ 1.31-1.66(2H, m), 1.70-2.05(6H, m), 2.19(3H, s), 2.38-2.60Example 2 step c (M + H) (3H, m), 2.73-2.83(2H, m), 2.85-3.11(2H, m),3.71-3.86(1H, m), 4.26-4.35(1H, m), 4.76-4.92(1H, m), 6.73(1H, d),7.07(1H, dd), 7.11(1H, s), 7.19-7.34(1H, m), 7.57(1H, t), 7.59-7.68(1H,m), 7.73(1H, t), 8.46(1H, d) 214 (IV) 514  96 (CDCl₃) δ 1.42-1.62(2H,m), 1.74-2.02(6H, m), 2.19(3H, s), 2.44-2.61 Example 2 step c (M + H)(3H, m), 2.75-2.85(3H, m), 2.95-3.11(1H, m), 3.42(2H, s), 3.45(3H, s),3.78-3.93(1H, m), 4.26-4.36(1H, m), 4.64-4.81(1H, m), 6.74(1H, d),7.02-7.15(3H, m), 7.27(1H, s), 7.38(1H, d) 589 (I) 540 (CDCl₃) δ1.52-1.62(2H, m), 1.68(1H, d), 1.84(1H, d), 1.92(2H, d), Example 2 stepc (M + H) 2.35-2.42(2H, m), 2.52-2.55(1H, m), 2.63(6H, s), 2.72-2.83(3H,m), 2.99-3.13(2H, m), 3.46-3.56(2H, m), 4.38-4.45(1H, m), 4.49 (1H, d),6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.73-7.75(2H, m), 7.81-7.83(1H,m), 8.31(1H, s) 590 (I) 556 (DMSO-D6) δ 1.43-1.62(4H, m), 1.66(1H, d),1.85(1H, d), 1.89-1.97 Example 2 step c (M + H) (2H, m), 2.35-2.44(3H,m), 2.73-2.87(3H, m), 3.11(1H, t), 3.42(3H, s), 3.52(1H, d),4.39-4.46(1H, m), 4.50(1H, d), 6.98(1H, dd), 7.25(1H, d), 7.49(1H, d),8.36(1H, t), 8.54(1H, t), 8.67(1H, t) 591 (I) 526 (DMSO-D6) δ1.29-1.39(2H, m), 1.90(2H, d), 2.11-2.18(1H, m), Example 2 step c (M +H) 2.39(2H, t), 3.13(2H, t), 3.44-3.52(2H, m), 3.65-3.73(2H, m),3.82-3.91(4H, m), 3.94-4.01(2H, m), 4.47-4.57(1H, m), 6.15 (1H, d),6.88-6.93(1H, m), 6.95(1H, dd), 7.03(1H, d), 7.31(1H, t), 7.62-7.65(1H,m), 8.32-8.51(2H, m), 8.95(1H, t) 593 (I) 536 (DMSO-D6) δ 1.42-1.63(4H,m), 1.66(1H, d), 1.84(1H, d), 1.89-1.97 Example 2 step c (M + H) (2H,m), 2.32-2.45(1H, m), 2.50-2.61(2H, m), 2.72-2.87(3H, m), 3.08(1H, t),3.37(3H, s), 3.48(1H, d), 4.37-4.46(1H, m), 4.46-4.55 (1H, m), 6.98(1H,dd), 7.25(1H, d), 7.49(1H, d), 8.21(1H, t), 8.30(1H, t), 8.48(1H, t) 594(I) 550 (DMSO-D6) δ 1.38-1.52(2H, m), 1.53-1.64(2H, m), 1.84(2H, d),Example 2 step c (M + H) 1.88-1.98(2H, m), 2.37-2.45(4H, m),2.58-2.68(1H, m), 2.74-2.82 (3H, m), 3.17(3H, s), 4.37-4.50(2H, m),6.99(1H, dd), 7.00-7.02 (1H, m), 7.26(1H, d), 7.49(1H, d), 7.61(1H, d),7.70(1H, dd), 8.23(1H, d) 299 (IV) 525 (DMSO-D6) δ 1.38-1.5(2H, m),1.60-1.70(2H, m), 1.81-2.00 Example 12 (M + H) (2H, m), 2.40(3H, s),2.41-3.31(9H, m), 3.35(3H, s), 3.41-3.58 (1H, m), 4.4-4.55(2H, m),7.09(1H, d), 7.34(1H, d), 7.71(2H, m), 7.90(1H, s), 8.0(1H, m) 300 (IV)489 (DMSO-D6) δ 1.10(3H, t), 1.35-1.50(2H, m), 1.58-1.70(2H, m), Example12 (M + H) 1.81-1.97(2H, m), 2.25-3.20(11H, m), 3.32(3H, s), 3.4-3.6(1H,m), 4.25-4.6(2H, m), 6.85-7.00(3H, m), 7.63-7.78(2H, m), 7.90 (1H, s),7.98-8.02(1H, m) 143 (IV) 465 (CDCl₃) δ 1.63-1.74(2H, m), 1.78-1.88(3H,m), 1.92-2.04(3H, Example 2 step c (M + H) m), 2.19(3H, s),2.43-2.55(2H, m), 2.64(1H, tt), 2.76-2.94(3H, m), 3.13-3.27(1H, m),4.25-4.35(2H, m), 4.82-4.90(1H, m), 6.74 (1H, d), 7.07(1H, dd), 7.11(1H,d), 7.56(1H, dd), 7.85(1H, d), 8.25 (1H, dd), 8.32(1H, d), 9.19(1H, dd)301 (IV) 530 (CDCl₃) δ 1.57-1.71(2H, m), 1.80-1.91(3H, m), 1.95-2.06(3H,Example 2 step c (M + H) m), 2.20(3H, s), 2.47-2.55(2H, m),2.61-2.72(1H, m), 2.79-2.86 (2H, m), 2.91-3.35(2H, m), 3.08(3H, s),4.28-4.37(1H, m), 4.69-4.80 (2H, m), 6.74(1H, d), 6.90(1H, d), 7.07(1H,dd), 7.12(1H, d), 7.57(1H, d), 7.79(1H, dd), 8.32(1H, d) 572 (I) 500(CDCl₃) δ 1.37-1.66(2H, m), 1.73-1.88(3H, m), 1.93-2.05(3H, Example 2step c (M + H) m), 2.41-2.51(2H, m), 2.52-2.63(1H, m), 2.75-2.86(2H, m),2.86-3.09 (2H, m), 3.71-3.90(1H, m), 4.23-4.32(1H, m), 4.77-4.93(1H, m),6.75(1H, dd), 6.99(1H, d), 7.27-7.32(3H, m), 7.54-7.67(1H, m), 7.57(1H,t), 7.74(1H, t), 8.46(1H, d) 120 (IV) 480 (CDCl₃) δ 1.46-1.66(2H, m),1.79-2.01(6H, m), 2.19(3H, s), 2.45-2.52 Example 2 step c using acidavailable (M + H) (2H, m), 2.59(1H, tt), 2.75-2.84(2H, m), 2.92-3.20(2H,m), from Bionet Research Ltd., Highfield 3.74-4.00(1H, m), 4.27-4.35(1H,m), 4.55-4.90(1H, m), 6.49 Industrial Estate, Camelford, (1H, dd),6.74(1H, d), 7.07(1H, dd), 7.11(1H, d), 7.76(1H, d), 7.88 Cornwall, PL329QZ, United (1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d) Kingdom 145(IV) 538 (CDCl₃) δ 1.35-1.73(2H, m), 1.77-1.89(3H, m), 1.92-2.06(3H,Example 2 step c using acid available (M + H) m), 2.19(3H, s),2.43-2.64(3H, m), 2.74-2.83(2H, m), 2.83-2.94 from Peakdale Inc. (1H,m), 3.00-3.12(1H, m), 3.38-3.54(1H, m), 4.26-4.35(1H, m), 109 EastScotland Drive 4.76-4.92(1H, m), 6.73(1H, d), 7.07(1H, dd), 7.11(1H, d),7.70 Bear, DE, 19701-1756 (1H, d), 7.98(1H, dd), 8.19(1H, d) USA 240(IV) 465 (CDCl₃) δ 1.62-1.74(2H, m), 1.77-1.86(3H, m), 1.93-2.03(3H,Example 2 step c (M + H) m), 2.33(3H, s), 2.41-2.54(2H, m), 2.65(1H,tt), 2.78-2.86(1H, m), 2.89(2H, td), 3.21(1H, td), 4.21-4.35(2H, m),4.81-4.90(1H, m), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.57(1H, dd),7.85(1H, d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd) 267 (IV) 453(CDCl₃) δ 1.62(2H, qd), 1.79-2.01(6H, m), 2.19(3H, s), 2.43-2.52 Example2 step c (M + H) (2H, m), 2.64(1H, tt), 2.74-2.85(2H, m), 3.12-3.22(1H,m), 4.26-4.32 (1H, m), 4.77-4.86(1H, m), 5.24-5.33(1H, m), 6.74(1H, d),6.84(1H, td), 7.07(1H, dd), 7.11(1H, d), 7.21(1H, dd), 7.23(1H, dd),7.60(1H, dd), 8.06(1H, d), 8.13(1H, dt) 199 (IV) 470 (CDCl₃) δ1.57-1.67(2H, m), 1.81-1.88(2H, m), 1.93-2.01(4H, Example 2 step c (M +H) m), 2.20(3H, s), 2.50(2H, td), 2.65(1H, tt), 2.82(2H, td), 2.96-3.20(2H, m), 4.28-4.35(1H, m), 4.74(2H, d), 6.73-6.75(2H, m), 7.01-7.12 (3H,m), 7.28(1H, d), 7.35(1H, dd), 9.35(1H, s) 181 (IV) 538 (CDCl₃) δ1.50-1.65(2H, m), 1.70-1.83(3H, m), 1.93-2.04(3H, Example 2 step c (M +H) m), 2.32(3H, s), 2.40-2.50(2H, m), 2.52-2.62(1H, m), 2.76-2.92 (3H,m), 3.01-3.10(1H, m), 3.38-3.52(1H, m), 4.22-4.30(1H, m), 4.77-4.90(1H,m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.70 (1H, d), 7.98(1H, dd),8.19(1H, d) 216 (IV) 526 (CDCl₃) δ 1.47-1.66(2H, m), 1.79-1.88(3H, m),1.95-2.04(3H, Example 2 step c (M + H) m), 2.32(3H, s), 2.53-2.61(2H,m), 2.70(1H, tt), 2.76-2.89(3H, m), 2.99-3.13(1H, m), 3.63-3.74(1H, m),4.27-4.33(1H, m), 4.63-4.77 (1H, m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H,d), 7.50(1H, dd), 7.56(1H, d), 8.09(1H, d) 266 (IV) 480 (CDCl₃) δ1.37-1.67(2H, m), 1.76-1.85(3H, m), 1.93-2.01(3H, Example 2 step c (M +H) m), 2.32(3H, s), 2.41-2.48(2H, m), 2.50-2.60(1H, m), 2.77-2.85 (2H,m), 2.86-3.10(2H, m), 3.73-3.85(1H, m), 4.23-4.29(1H, m), 4.77-4.92(1H,m), 6.67(1H, dd), 6.77(1H, d), 7.20(1H, d), 7.21-7.31 (1H, m),7.54-7.68(1H, m), 7.56(2H, t), 7.73(1H, t), 8.46(1H, d) 540 (I) 485(CDCl₃) δ 1.69-1.84(4H, m), 1.95-2.02(4H, m), 2.43-2.53(2H, Example 2step c (M + H) m), 2.65(1H, tt), 2.79-2.93(3H, m), 3.18-3.25(1H, m),4.23-4.35 (2H, m), 4.82-4.90(1H, m), 6.75(1H, dd), 7.00(1H, d), 7.31(1H,d), 7.57(1H, dd), 7.86(1H, d), 8.25(1H, dd), 8.32(1H, d), 9.19(1H, dd)204 (IV) 470 (CDCl₃) δ 1.57-1.67(2H, m), 1.77-1.85(2H, m), 1.94-2.02(4H,Example 2 step c (M + H) m), 2.33(3H, s), 2.45-2.52(2H, m),2.61-2.69(1H, m), 2.81-2.86 (2H, m), 2.97-3.18(2H, m), 4.24-4.30(1H, m),4.74(2H, d), 6.68 (1H, dd), 6.73(1H, d), 6.78(1H, d), 7.04(1H, td),7.20(1H, d), 7.28 (1H, d), 7.35(1H, dd), 9.34(1H, s). 104 (IV) 480(CDCl₃) δ 1.49-1.63(2H, m), 1.76-2.00(6H, m), 2.33(3H, s), 2.43-2.49Example 2 step c (M + H) (2H, m), 2.59(1H, tt), 2.79-2.85(3H, m),3.00-3.18(1H, m), 3.81-3.96(1H, m), 4.24-4.29(1H, m), 4.67-4.83(1H, m),6.49 (1H, dd), 6.67(1H, dd), 6.78(1H, d), 7.20(1H, d), 7.76(1H, d), 7.88(1H, dd), 8.03(1H, d), 8.48(1H, d), 8.57(1H, d) 243 (IV) 486(DMSO-D6/CDCl₃) δ 1.43-1.59(2H, m), 1.73-1.98(6H, m), 2.32 Example 2step c (M + H) (3H, s), 2.43-2.48(2H, m), 2.79-2.87(2H, m),2.91-3.40(5H, m), 4.23-4.30(1H, m), 6.68(1H, dd), 6.78(1H, d), 7.14(1H,d), 7.19 (1H, d), 7.26(1H, dd), 7.43(1H, d), 7.51(1H, s). 191 (IV) 514(CDCl₃) δ 1.46-1.59(2H, m), 1.76-2.00(6H, m), 2.32(3H, s), 2.44-2.48Example 2 step c (M + H) (2H, m), 2.54-2.59(1H, m), 2.78-2.85(3H, m),3.42(3H, s), 3.45(3H, s), 3.79-3.92(1H, m), 4.23-4.30(1H, m),4.67-4.79(1H, m), 6.67(1H, dd), 6.77(1H, d), 7.02(1H, d), 7.15(1H, s),7.20(1H, d), 7.37(1H, d) 519 (I) 490 (CDCl₃) δ 1.61(2H, qd),1.77-1.85(2H, m), 1.94-2.02(4H, m), 2.38-2.51 Example 2 step c (M + H)(2H, m), 2.65(1H, tt), 2.80-2.85(2H, m), 2.95-3.14(2H, m), 4.25-4.30(1H,m), 4.73-4.77(2H, m), 6.73(1H, d), 6.75(1H, dd), 7.00(1H, d), 7.03(1H,td), 7.27(1H, dd), 7.31(1H, d), 7.35(1H, dd), 9.49(1H, s) 494 (I) 558(CDCl₃) δ 1.48-1.71(2H, m), 1.74-1.83(3H, m), 1.93-2.03(3H, Example 2step c (M + H) m), 2.42-2.50(2H, m), 2.55-2.62(1H, m), 2.76-2.93(3H, m),3.01-3.10 (1H, m), 3.40-3.50(1H, m), 4.22-4.31(1H, m), 4.77-4.90(1H, m),6.75(1H, dd), 6.98(1H, d), 7.30(1H, d), 7.67(1H, d), 7.98(1H, dd),8.19(1H, d) 238 (IV) 511 172-173 (CDCl₃) δ 1.53-1.63(2H, m),1.82-1.89(3H, m), 2.00-2.05(3H, Example 21 (M + H) m), 2.05-2.61(3H, m),2.80-2.84(3H, m), 2.98-3.09(1H, m), 3.03 (3H, s), 3.77(1H, br s),4.41-4.45(1H, m), 4.70(1H, br s), 6.99(2H, d), 7.21-7.26(1H, m),7.44-7.54(2H, m), 7.86(2H, d) 496 (I) 500 (DMSO-D6) δ 1.46(2H, qd),1.54-1.61(2H, m), 1.65-1.88(3H, m), Example 2 step c (M + H)1.89-1.97(2H, m), 2.37-2.42(2H, m), 2.54-2.61(1H, m), 2.73-2.83 (2H, m),3.04-3.17(1H, m), 3.61-3.72(1H, m), 4.39-4.56(2H, m), 6.62(1H, dd),6.98(1H, dd), 7.25(1H, d), 7.49(1H, d), 7.87(1H, dd), 7.97(1H, dd),8.04(1H, dd), 8.52(1H, dd), 8.65(1H, dd) 483 (I) 506 (DMSO-D6) δ1.41(2H, qd), 1.53-1.62(2H, m), 1.68-1.82(2H, m), Example 2 step c (M +H) 1.89-1.96(2H, m), 2.36-2.43(3H, m), 2.53-2.59(3H, m), 2.74-2.80 (3H,m), 4.39-4.45(1H, m), 6.97(1H, dd), 7.13(1H, d), 7.25 (1H, d), 7.30(1H,dd), 7.49(1H, d), 7.66(1H, d) 302 (IV) 498 (CDCl₃) δ 1.40-1.74(2H, m),1.79-2.02(6H, m), 2.20(3H, s), 2.42-2.61 Example 2 step c (M + H) (3H,m), 2.67(1H, td), 2.74-2.84(2H, m), 3.16(1H, t), 3.91-4.00 (1H, m),4.26-4.36(1H, m), 4.58-4.78(5H, m), 6.74(1H, d), 6.76-6.79(1H, m),6.98-7.02(3H, m), 7.07(1H, dd), 7.12(1H, d) 303 (IV) 498 (CDCl₃) δ1.42-1.61(2H, m), 1.77-1.90(3H, m), 1.93-2.03(3H, Example 2 step c (M +H) m), 2.33(3H, s), 2.41-2.49(2H, m), 2.57(1H, tt), 2.67(1H, t),2.77-2.84 (2H, m), 3.16(1H, t), 3.95(1H, d), 4.24-4.29(1H, m), 4.59-4.77(5H, m), 6.68(1H, dd), 6.75-6.79(2H, m), 6.97-7.00(3H, m), 7.21(1H, d)596 (I) 518 (CDCl₃) δ 1.43-1.64(2H, m), 1.77-1.89(3H, m), 1.94-2.01(3H,Example 2 step c (M + H) m), 2.41-2.50(2H, m), 2.57(1H, tt), 2.68(1H,t), 2.76-2.83(2H, m), 3.16(1H, t), 3.94-3.97(1H, m), 4.24-4.30(1H, m),4.58-4.63(1H, m), 4.68(2H, s), 4.76(2H, d), 6.76-6.78(2H, m),6.98-7.00(3H, m), 7.26(1H, s), 7.31(1H, d) 467 (I) 534 (DMSO-D6) δ1.35-1.50(2H, m), 1.52-1.65(3H, m), 1.68-1.84 Example 2 step c (M + H)(2H, m), 1.88-1.98(2H, m), 2.35-2.44(2H, m), 2.54-2.61(1H, m),2.73-2.82(3H, m), 3.37(3H, s), 3.57(2H, s), 3.60-3.71(1H, m),4.38-4.56(2H, m), 6.98(1H, dd), 7.07(1H, dd), 7.24(1H, d), 7.26 (1H, d),7.47(1H, d), 7.50(1H, d) 269 (IV) 453 (CDCl₃) δ 1.55-1.68(4H, m),1.75-2.01(4H, m), 2.33(3H, s), 2.41-2.51 Example 2 step c (M + H) (2H,m), 2.64(1H, tt), 2.78-2.87(3H, m), 3.12-3.24(1H, m), 4.21-4.29(1H, m),4.76-4.88(1H, m), 5.23-5.34(1H, m), 6.67 (1H, dd), 6.78(1H, d), 6.84(1H,t), 7.19-7.26(2H, m), 7.60(1H, d), 8.06(1H, s), 8.13(1H, dd) 597 (I) 546(CDCl₃) δ 1.39-1.66(2H, m), 1.73-1.86(4H, m), 1.92-2.03(2H, Example 2step c (M + H) m), 2.41-2.50(2H, m), 2.53-2.63(1H, m), 2.76-2.88(2H, m),2.98-3.12 (1H, m), 3.62-3.77(1H, m), 4.24-4.29(1H, m), 4.62-4.78(1H, m),6.75(1H, dd), 6.99(1H, d), 7.31(2H, d), 7.53(1H, dd), 7.57(1H, t),8.12(1H, d) 598 (I) 474 CDCl₃) δ 1.58-1.75(2H, m), 1.80-1.88(2H, m),1.91-2.05(4H, Example 2 step c (M + H) m), 2.53-2.61(2H, m),2.71-2.90(4H, m), 3.18-3.22(1H, m), 4.27-4.33 (1H, m), 4.84(1H, d),5.55(1H, d), 6.75(1H, dd), 6.95(1H, dd), 7.00(1H, d), 7.31(1H, d),8.09(1H, s), 8.46(1H, dd), 8.62(1H, dd) 579 (I) 491 (CDCl₃) δ 1.61(1H,qd), 1.75-2.02(7H, m), 2.42-2.51(2H, m), 2.59-2.67 Example 2 step c (M +H) (1H, m), 2.75-2.86(3H, m), 3.12-3.21(1H, m), 4.23-4.29 (1H, m),4.76-4.85(1H, m), 5.23-5.32(1H, m), 6.75(1H, dd), 6.99 (1H, d), 7.16(1H,ddd), 7.30(1H, d), 7.58(1H, dd), 8.07(2H, s) 599 (I) 487 (CDCl₃) δ1.58-1.67(1H, m), 1.75-2.02(7H, m), 2.43-2.51(3H, Example 2 step c (M +H) m), 2.59-2.68(1H, m), 2.61(3H, s), 2.76-2.85(3H, m), 3.12-3.23 (1H,m), 4.23-4.28(1H, m), 4.78-4.87(1H, m), 5.30-5.38(1H, m), 6.67(1H, d),6.75(1H, dd), 7.20(1H, dd), 7.30(1H, d), 7.51(1H, d), 8.01(1H, s) 600(I) 507 (CDCl₃) δ 1.61(1H, qd), 1.70-2.04(7H, m), 2.41-2.53(2H, m), 2.63Example 2 step c (M + H) (1H, t), 2.73-2.88(3H, m), 3.09-3.23(1H, m),4.21-4.31(1H, m), 4.74-4.86(1H, m), 5.20-5.30(1H, m), 6.75(1H, dd),6.99(1H, d), 7.19(1H, d), 7.30(1H, d), 7.55(1H, d), 8.04(1H, s),8.19(1H, s) 304 (IV) 505 CDCl₃) δ 1.57-1.68(2H, m), 1.82-2.01(6H, m),2.46-2.54(2H, Example 2 step c (M + H) m), 2.46(3H, s), 2.59-2.69(1H,m), 2.73-2.90(3H, m), 3.10-3.23 (1H, m), 4.32-4.39(1H, m), 4.76-4.85(1H,m), 5.22-5.32(1H, m), 6.75(1H, d), 7.14-7.27(2H, m), 7.58(1H, dd),8.07(2H, s) 601 (I) 487 (CDCl₃) δ 1.55-1.65(1H, m), 1.75-2.01(7H, m),2.40(3H, s), 2.44 -2.50 Example 2 step c (M + H) (2H, m), 2.63(1H, qt),2.73-2.86(3H, m), 3.10-3.22(1H, m), 4.22-4.28(1H, m), 4.75-4.86(1H, m),5.22-5.34(1H, m), 6.66 (1H, dd), 6.75(1H, dd), 6.99(1H, d), 7.30(1H, d),7.34(1H, s), 7.97 (1H, s), 7.99(1H, d) 343 (I) 566 (CDCl₃) δ1.39-1.65(1H, m), 1.77-1.89(4H, m), 1.94-2.03(3H, Example 2 step c (M +H) m), 2.43-2.50(2H, m), 2.54-2.62(1H, m), 2.77-2.90(3H, m), 3.03-3.13(1H, m), 3.53(3H, s), 3.65-3.74(1H, m), 4.26-4.31(1H, m), 4.26(2H, s),4.69-4.79(1H, m), 6.75(1H, dd), 6.99(1H, d), 7.26-7.35 (3H, m), 8.00(1H,d) 603 (I) 526 (CDCl₃) δ 1.49-1.58(2H, m), 1.76-1.84(3H, m),1.90-2.01(4H, Example 2 step c (M + H) m), 2.44-2.48(2H, m),2.53-2.59(1H, m), 2.78-2.82(2H, m), 2.78-3.00 (5H, m), 3.15-3.19(1H, m),4.24-4.29(1H, m), 4.96(2H, s), 6.74-6.80(2H, m), 6.99(1H, d), 7.31(1H,d), 7.66-7.70(2H, m) 534 (I) 543 (CDCl₃) δ 1.49(3H, t), 1.57-2.00(6H,m), 2.43-2.52(2H, m), 2.56-2.62 Example 2 step c (M + H) (3H, m),2.67(3H, s), 2.78-2.84(3H, m), 3.10-3.19(1H, m), 3.74(1H, d), 4.25(1H,dquintet), 4.42-4.49(2H, m), 4.76(1H, d), 6.75(1H, dd), 6.99(1H, d),7.23(1H, d), 7.30(1H, d), 8.09(1H, s), 8.60(1H, d)  5 (II) 474 Example 2step c (M + H)  6 (II) 468 (DMSO-D6) δ 1.39-1.45(1H, m), 1.54-1.93(6H,m), 2.32-2.39 Example 2 step c (2H, m), 2.49-2.53(2H, m), 2.72-3.02(4H,m), 3.29-3.32(2H, m), 4.31-4.34(1H, m), 6.75-6.79(1H, m), 7.08(1H, ddd),7.30(2H, dt), 7.49-7.56(2H, m), 7.76(1H, t), 8.24(1H, dd)  7 (II) 453(DMSO-D6) δ 1.45-1.69(5H, m), 1.84-1.99(3H, m), 2.40(2H, t), Example 2step c (M + H) 2.59-2.66(1H, m), 2.73-2.92(3H, m), 3.03-3.14(1H, m),3.69-3.76 (1H, m), 4.31-4.37(1H, m), 4.55-4.61(1H, m), 6.78(1H, dd),7.09(1H, ddd), 7.31(1H, dt), 7.69-7.78(2H, m), 8.49-8.65(2H, m),9.15(1H, dd)  8 (II) 441 (DMSO-D6) δ 1.34-1.45(2H, m), 1.52-1.61(2H, m),1.76-1.86 Example 2 step c (M + H) (2H, m), 1.87-1.96(2H, m),2.33-2.44(2H, m), 2.56-2.63(1H, m), 2.72-2.81(3H, m), 3.05-3.14(1H, m),4.29-4.38(1H, m), 4.51-4.61 (1H, m), 5.09-5.19(1H, m), 6.73-6.79(1H, m),6.94-6.99 (1H, m), 7.04-7.12(1H, m), 7.28-7.34(2H, m), 7.61(1H, dd),8.30 (1H, s), 8.56(1H, dt) 305 (IV) 514 DMSO-D6) δ 1.42-1.51(2H, m),1.60-1.93(6H, m), 2.41-2.47 Example 2 step c (M + H) (2H, m), 2.41(3H,s), 2.54-2.60(1H, m), 2.72-2.80(2H, m), 3.05-3.15 (1H, m), 3.29-3.35(1H,m), 3.60-3.71(1H, m), 4.44-4.54(2H, m), 6.59-6.64(1H, m), 7.07-7.13(1H,m), 7.31-7.38(1H, m), 7.86-7.89 (1H, m), 7.95-7.99(1H, m), 8.01-8.07(1H,m), 8.50-8.54(1H, m), 8.63-8.67(1H, m) 306 (IV) 531 (DMSO-D6) δ1.39-1.95(8H, m), 2.40(3H, s), 2.42-2.47(2H, m), Example 2 step c (M +H) 2.55-2.63(2H, m), 2.72-2.81(2H, m), 2.94-3.09(2H, m), 3.42(3H, s),4.14-4.32(1H, m), 4.46-4.54(1H, m), 7.10(1H, d), 7.36(1H, d), 7.49(1H,d), 7.78(1H, d) 307 (IV) 525 (DMSO-D6) δ 1.39-1.95(9H, m), 2.42(3H, s),2.44-2.48(1H, m), Example 2 step c (M + H) 2.55-2.61(1H, m),2.70-2.83(2H, m), 2.99-3.10(1H, m), 3.29 (3H, s), 3.41-3.52(2H, m),4.46-4.58(2H, m), 7.11(1H, d), 7.36 (1H, d), 7.66(2H, dd), 7.99(2H, dd)308 (IV) 512 (DMSO-D6) δ 1.60-4.25(18H, m), 4.55-4.80(1H, m),5.22-5.45(1H, Prepared in a similar manner to (M + H) m), 7.05(1H, t),7.75-7.82(2H, m), 7.85(1H, s), 8.00-8.18(2H, m), Example 15 and isolatedas the 8.60(1H, s), 9.63(1H, br s) trifluoroacetate salt  1 (V) 50987-88 (DMSO-D⁶) δ 1.11-1.18(2H, m), 1.36-1.53(4H, m), 1.63-1.78 Example2 step c (M + H) (2H, m), 2.07(2H, t), 2.48-2.52(2H, m), 2.81-2.84(4H,m), 3.01-3.04 (2H, m), 3.27-3.27(3H, m), 3.49-3.50(1H, m), 4.44-4.53(1H,m), 7.15-7.18(1H, m), 7.44-7.45(1H, m), 7.50-7.53(1H, m), 7.69-7.76 (2H,m), 7.90(1H, t), 7.98-8.02(1H, m)  2 (V) 510 (CDCl₃) δ 1.38-1.48(3H, m),1.59(1H, br s), 1.81-2.07(4H, m), Example 12 (M + H) 2.34(2H, t),2.55-2.60(1H, m), 2.84-2.92(3H, m), 3.07(4H, s), 3.21 (1H, br s),3.60(1H, d), 3.68(1H, br s), 4.74(1H, br s), 6.41(1H, dd), 6.64(1H, d),7.16(1H, d), 7.62-7.70(2H, m), 7.97-8.02(2H, m)  3 (V) 523 (DMSO-D6) δ1.42-1.56(4H, m), 1.64-1.86(4H, m), 2.33(2H, t), Prepared in a similarmaner to (M + H) 2.54-2.61(1H, m), 2.76-2.85(1H, m), 2.87-2.93(2H, m),3.04-3.12 Example 12 using (3, 4-Dichloro- (1H, m), 3.28(3H, s),3.36-3.44(1H, m), 3.48-3.57(1H, m), phenyl)-piperidin-4-yl-methanone4.47-4.55(1H, m), 7.70-7.77(2H, m), 7.80(1H, d), 7.91-7.95(2H,hydrochloride (free base was made m), 8.00(1H, dt), 8.14-8.16(1H, m)insitu using triethylamine 310 (IV) 478 169-170 (DMSO-D6) δ1.29-1.40(2H, m), 1.53-1.62(2H, m), 1.71-1.77 Example 26 using 4- (M +H) (2H, m), 1.89-1.96(2H, m), 2.35-2.42(2H, m), 2.45-2.49(1H, m),Methoxyphenylisocyanate 2.68-2.79(4H, m), 3.70(3H, s), 4.10-4.17(2H, m),4.38-4.45(1H, m), 6.78-6.82(2H, m), 6.98(1H, dd), 7.25(1H, d),7.30-7.34(2H, m), 7.49(1H, d), 8.30(1H, s) 311 (IV) 466 217 (DMSO-D6) δ1.29-1.40(2H, m), 1.53-1.62(2H, m), 1.72-1.78 Example 26 using 4- (M +H) (2H, m), 1.89-1.96(2H, m), 2.36-2.42(2H, m), 2.44-2.49(1H, m),Fluorophenylisocyanate 2.71-2.79(4H, m), 4.11-4.17(2H, m), 4.38-4.45(1H,m), 6.98 (1H, dd), 7.05(2H, t), 7.25(1H, d), 7.45(2H, tt), 7.49(1H, d),8.50(1H,s) 312 (IV) 494 170-172 DMSO-D6) δ 1.29-1.40(2H, m),1.52-1.62(2H, m), 1.72-1.78 Example 26 using 3- (M + H) (2H, m),1.89-1.96(2H, m), 2.36-2.42(2H, m), 2.43(3H, s), 2.44-2.48(Methylthio)phenylisocyanate (1H, m), 2.71-2.79(4H, m), 4.15(2H, d),4.38-4.45(1H, m), 6.81(1H, d), 6.98(1H, dd), 7.15(1H, t), 7.24-7.27(2H,m), 7.43(1H, t), 7.49(1H, d), 8.48(1H, s) 313 (IV) 462 178-179 (DMSO-D6)δ 1.22-1.34(2H, m), 1.52-1.61(2H, m), 1.65-1.72 Example 26 usingBenzylisocyanate (M + H) (2H, m), 1.88-1.95(2H, m), 2.33-2.46(3H, m),2.61-2.76(4H, m), 3.99-4.05(2H, m), 4.22(2H, d), 4.37-4.44(1H, m),6.97(1H, dd), 7.04(1H, t), 7.18-7.31(6H, m), 7.49(1H, d) 314 (IV) 492166-167 (DMSO-D6) δ 1.21-1.32(2H, m), 1.51-1.61(2H, m), 1.64-1.71Example 26 using 4- (M + H) (2H, m), 1.88-1.95(2H, m), 2.32-2.46(3H, m),2.59-2.67(2H, m), Methoxybenzylisocyanate 2.69-2.76(2H, m), 3.71(3H, s),4.01(2H, d), 4.14(2H, d), 4.37-4.44 (1H, m), 6.83-6.87(2H, m),6.94-6.99(2H, m), 7.14-7.18(2H, m), 7.25(1H, d), 7.49(1H, d) 315 (IV)480 209-210 (DMSO-D6) δ 1.21-1.32(2H, m), 1.52-1.61(2H, m), 1.65-1.71Example 26 using 4- (M + H) (2H, m), 1.88-1.95(2H, m), 2.32-2.46(3H, m),2.60-2.68(2H, m), Fluorobenzylisocyanate 2.70-2.76(2H, m), 4.01(2H, d),4.19(2H, d), 4.38-4.44(1H, m), 6.97(1H, dd), 7.05(1H, t), 7.11(2H, t),7.24-7.29(3H, m), 7.49(1H, d) MS = Mass Spectrum has been obtained usingeither APCI+ or ES+ or ES−

The preparations of certain intermediates are now presented.

Method A 1-(3-Methoxy-4-nitro-benzoyl)-piperidin-4-one

CDI (9 g) added to a solution of 3-methoxy-4-nitrobenzoic acid (10 g)stirring in THF (200 ml) at RT. After 1 hour, 4-piperidone hydrochloride(6.9 g) and triethylamine (7.8 ml) were added and the mixture stirredovernight. The mixture was diluted with ethyl acetate, washed with 2NHCl (100 ml) then saturated NaHCO₃ solution (200 ml) then saturatedbrine (200 ml). The organic layer was dried (MgSO₄) and evaporated toleave a residue which was purified by column chromatography (silica,mixtures of MeOH in dichloromethane) to give the product as a yellowsolid (8.5 g; MS: APCI⁺(M+H) 279).

Method B 1-(3-Methanesulfonyl-benzoyl)-piperidin-4-one

PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonylbenzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base(25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture wasstirred overnight then washed with saturated NaHCO₃ solution (200 ml)and then with saturated brine (200 ml). The organic layer was evaporatedand the resulting residue purified by column chromatography (silica, 1:1ethyl acetate: dichloromethane) to give the product as a thick oil (9.6g; MS: APCI⁺(M+H) 282).

Method C 1-(Benzo[1,2,3]thiadiazole-5-carbonyl)-piperidin-4-one

CDI (4.5 g) added to a solution of thebenzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml)at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine(4.3 ml) were added and the mixture stirred overnight. The resultingmixture was diluted with ethyl acetate, washed with 2M HCl (100 ml),saturated NaHCO₃ solution (200 ml) and then with saturated brine (200ml). The organic layer was dried (MgSO₄) and evaporated to leave aresidue which was purified by column chromatography (silica, elutingwith mixtures of ethyl acetate in dichloromethane) to give the productas a yellow oil (2.1 g; MS: APCI⁺(M+H)262).

Method D [1,4′]Bipiperidinyl-4-ol

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200ml) with acetic acid (4 ml) at RT for 30 minutes. Sodiumtriacetoxyborohydride (23 g) was then added and the mixture stirred atRT overnight. The mixture was evaporated to dryness and the residuetaken into water, extracted with diethyl ether (3×200 ml), the aqueouswas basified to pH 9-10 and extracted with dichloromethane (3×200 ml).The dichloromethane extracts were combined, dried (MgSO₄) and evaporatedto leave an oil (19 g; same compound as Example 9 step 1). The oil wasdissolved in methanol (300 ml) and treated with concentratedhydrochloric acid (5 ml). The mixture was stirred overnight and thenevaporated to dryness to leave the title compound as the hydrochloridesalt (15 g).

¹H NMR (400 MHz, DMSO-D6) δ 1.6-2.4 (m, 9H), 2.8-3.5 (m, 8H), 3.62 (m,1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).

Method E(4-Hydroxy-[1,4′]bipiperidinyl-1′-yl)-(3-methanesulfonyl-phenyl)-methanone

PyBrOP™ (25.3 g) was added to a stirred solution of 3-methanesulphonylbenzoic acid (10 g), [1,4′]bipiperidinyl-4-ol dihydrochloride (13 g, seeMethod D) and Hunig's base (34 ml) in dichloromethane (500 ml). Theresulting mixture was stirred at RT overnight, then washed withsaturated NaHCO₃ solution (300 ml) followed by saturated brine (300 ml).The organic layer was dried (MgSO₄) and evaporated to leave an oilyresidue. Column chromatography (silica, 20% methanol in DCM) gave theproduct as a white solid (16 g; MS: APCI⁺(M+H) 367).

Method F 4-(3-Chloro-4-fluoro-phenoxy)-piperidine

DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g),3-chloro-4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester (0.5 g) in THF at RT. The resulting mixture wasstirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixturestirred at RT overnight. The mixture was then evaporated to dryness andtriethylamine (5 ml) was added. The mixture was evaporated and theresidue was dissolved in methanol (10 ml), placed onto a SCX cartridge(Varian, 10 g, SCX cartridge available from International SorbentTechnology Isolute® Flash SCX-2) and eluted: first with methanol thenwith 10% NH₃ in methanol. The basic fractions were combined andevaporated to give the product as an oil (0.6 g).

¹H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.46 (2H, m), 1.83-1.91 (2H, m),2.53-2.59 (2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H,septet), 6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).

The following intermediates were prepared in similar manner to Method F:

MS: (M + H) 4-(4-chloro-2-methyl-phenoxy)-piperidine 2264-(4-chloro-3-fluoro-phenoxy)-piperidine 2304-(4-chloro-2-methoxy-phenoxy)-piperidine 2424-(4-fluoro-2-methoxy-phenoxy)-piperidine 2264-(4-methoxy-phenoxy)-piperidine 208 4-p-tolyloxy-piperidine 1924-(4-chloro-3-methyl-phenoxy)-piperidine 2264-(4-chloro-phenoxy)-piperidine 212 4-(4-fluoro-phenoxy)-piperidine 1964-(2,4-dichloro-phenoxy)-piperidine 2464-(2-chloro-4-fluoro-phenoxy)-piperidine 2304-(2,4-difluoro-phenoxy)-piperidine 2144-(4-chloro-2-fluoro-phenoxy)-piperdine 2304-(4-fluoro-2-methyl-phenoxy)-piperidine 2104-(4-chloro-2,6-dimethyl-phenoxy)-piperdine 2404-(2,3-dichloro-phenoxy)-piperidine 2464-(2,5-dichloro-phenoxy)-piperidine 2464-(2-chloro-4-methyl-phenoxy)-piperdine 2264-(2-chloro-5-methyl-phenoxy)-piperidine 2261-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone 2344-(2-chloro-6-methyl-phenoxy)-piperidine 2264-[2-(piperidin-4-yloxy)-phenyl]-morpholine 2634-(4-chloro-2-ethyl-phenoxy)-piperidine 2407-(piperidin-4-yloxy)-quinoline 229 4-(2-tert-butyl-phenoxy)-piperidine234 4-(indan-5-yloxy)-piperidine 2184-(4-chloro-2-cyclohexyl-phenoxy)-piperdine 2945-chloro-2-(piperidin-4-yloxy)-benzamide 2554-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine 2794-(5-chloro-2-methyl-phenoxy)-piperdine 226 4-phenoxy-piperidine 1784-(2,4-dichloro-6-methyl-phenoxy)-piperidine 2604-(3-chloro-4-methyl-phenoxy)-piperidine 2265-chloro-2-(piperidin-4-yloxy)-benzonitrile 2374-(2,4-dichloro-3-methyl-phenoxy)-piperidine 2604-(2-ethyl-4-fluoro-phenoxy)-piperidine 2244-(4-methanesulfonyl-phenoxy)-piperidine 297

Method G 4-Amino-3-ethoxy-benzoic acid

Potassium hydroxide (0.278 g) was added to a solution of3-fluoro-4-nitrobenzoic acid (0.4 g) in ethanol (7 ml) and the reactiontreated with microwaves (300 W, 100° C.) for 5 minutes. The reactionmixture was acidified using 2N HCl and extracted with ethyl acetate. Theextracts were combined, washed with water, dried (MgSO₄) and evaporatedto give 3-ethoxy-4-nitro-benzoic acid (0.325 g).

3-Ethoxy-4-nitrobenzoic acid (0.31 g) was treated with 5% palladium oncharcoal under an atmosphere of hydrogen (1 bar) for 3 hours. Thereaction mixture was filtered and the filtrate was evaporated to leavethe product as a beige solid (0.245 g; MS: ES⁻(M−H) 180).

Method H 3,4-bis-Methanesulfonyl-benzoic acid

To 3-fluoro-4-nitro-benzoic acid tert-butyl ester (0.5 g) in DMSO wasadded NaSO₂Me. The reaction mixture was heated to 100° C. for 24 hours.A mixture of water, diethyl ether and ethyl acetate (1:1:1) was addedand the resulting mixture was extracted with diethyl ether/ethyl acetate(1:1). The organic extracts were combined, dried with MgSO₄ andconcentrated to leave a residue which was purified by chromatography(using 80% ethyl acetate/20% hexane) to give3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (366 mg). ¹H NMR(399.98 MHz, DMSO-D6) 1.59 (9H, s), 3.50 (3H, s) 3.52 (3H, s), 8.37-8.65(3H, m).

To 3,4-bis-methanesulfonyl-benzoic acid tert-butyl ester (0.366 g) indichloromethane was added trifluoroacetic acid and the reaction mixturewas stirred for 3 hours. The mixture was evaporated and trituration ofthe residue with diethyl ether gave the title compound (0.29 g; MS:APCI⁺(M+H) 279).

Method I 4-Carbamoyl-5-methanesulfonyl-thiophene-2-carboxylic acid

To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester(0.5 g) in THF/H₂0 (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloricacid (2M) was added and the resulting mixture was extracted with ethylacetate. The extracts were combined and the solvent evaporated to leavea mixture of 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid andthe title compound. This mixture was used without further purification.¹H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).

Method J 3-(2-Methyl-propane-1-sulfonyl)-benzoic acid

To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate(1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65ml). The mixture was heated by microwaves (600W) at 150° C. for 15minutes. The reaction mixture was partitioned between water (100 ml) andethyl acetate (100 ml), the aqueous layer was separated, acidified to pH1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extractwas evaporated to leave a residue which was purified by flashchromatography (Biotage 12S eluting with ethyl acetate:hexane:aceticacid, 29:70:1) to give the title product as a white solid (0.34 g).

¹H NMR: (399.98 MHz, DMSO-D6) δ 0.98 (6H, d), 2.03 (1H, septet), 3.29(2H, d), 7.81 (1H, t), 8.16 (1H, ddd), 8.27 (1H, dt), 8.38 (1H, t).

3-Cyclopropylmethanesulfonyl-benzoic acid was prepared in a similarmanner to that described in Method J. MS: (M−H) 239; ¹H NMR: (DMSO-d6) δ0.06-0.10 (2H, m), 0.40-0.45 (2H, m), 0.82-0.89 (1H, m), 3.34 (2H, d),7.80 (1H, t), 8.14 (1H, d), 8.39 (1H, s).

Method K 3-(2-Methoxy-ethoxy)-benzoic acid methyl ester

To a solution of methyl 3-hydroxybenzoate (5.7 g) and 2-bromoethylmethylether (5.2 g) in dimethylformamide (100 ml) was added caesium carbonate(24.3 g). The reaction mixture was stirred for 12 hours. The mixture wasthen patitioned between ethyl acetate (400 ml) and water (400 ml). Theorganic layer was separated, dried (MgSO₄) and the solvent removed underreduced pressure. The residue was purified by flash chromatography(Biotage 12M, eluting iso-hexane then MeOH:dichloromethane 2:98) to givethe product as a colourless oil (5.3 g).

¹H NMR: (CDCl₃) δ 3.44 (3H, s), 3.75 (2H, t), 3.89 (3H, s), 4.15 (2H,t), 7.13 (1H, ddd), 7.32 (1H, t), 7.57 (1H, dd), 7.62 (1H, dt).

3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester can be preparedin a similar manner to that described in Method K: ¹H NMR: (299.944 MHzCDCl₃) 1.49 (9H, s), 3.91 (3H, s), 4.56 (2H, s), 7.13-7.68 (4H, m).

Method L 3-(2-Methoxy-ethoxy)-benzoic acid

To a suspension of 3-(2-methoxy-ethoxy)-benzoic acid methyl ester (5.3g) in tetrahydrofuran (200 ml) was added lithium hydroxide monohydrate(5.3 g) followed by water until an homogeneous solution was obtained.The reaction mixture was stirred for 12 hours, acidified and partitionedbetween ethyl acetate (200 ml) and water (200 ml). The organic layer wasseparated, dried (MgSO₄) and the solvent removed under reduced pressureto yield a colourless solid (3.6 g).

¹H NMR: (DMSO-D6) δ 3.31 (3H, s), 3.67 (2H, t), 4.14 (2H, t), 7.20 (1H,ddd), 7.41 (1H, t), 7.44 (1H, dd), 7.53 (1H, dt)

3-(2-tert-Butoxycarbonylamino-ethoxy)-benzoic acid can be prepared in asimilar manner to that described in Method L.

3-tert-Butoxycarbonylmethoxy-benzoic acid can be prepared in a similarmanner to that described in Method L: ¹H NMR (299.944 MHz, DMSO-D6) δ2.51 (9H, s), 4.74 (2H, s), 7.18 (1H, dq), 7.38 (1H, m), 7.41 (1H, m),7.55 (1H, dt), 13.03 (1H, s).

Method M 4-(2-Carboxy-2-phenyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

Piperazine-1-carboxylic acid tert-butyl ester (17.43 g) and2-phenylacrylic acid (18 g) in iso-propanol (500 ml) was heated atreflux for four days. The resulting precipitate was filtered, washedwith diethyl ether and dried under vacuum to give the title compound asa white solid (17 g; MS: APCI⁺(M+H) 335).

Method N 5-Methanesulfonyl-1H-indole-2-carboxylic acid

To a solution of the 5-methanesulfonyl-1H-indole-2-carboxylic acidmethyl ester (0.49 g) in THF (12 mL) and water (4 ml) was added LiOH(0.098 g). The reaction mixture was left to stir for 2 hours. Aceticacid was added and the product extracted with dichloromethane. Theorganic extracts were combined, dried with magnesium sulfate, filteredand the filtrate evaporated to give the title compound as a solid (0.110g).

¹H NMR (299.946 MHz, DMSO-D6) δ 3.18 (3H, s), 7.32-7.33 (1H, m),7.61-7.64 (1H, m), 7.73-7.77 (1H, m), 8.30-8.31 (1H, m).

Method O

5-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid was prepared in asimilar manner to 6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (seeExample 25) using the commercially available5-methyl-1,8a-dihydro-imidazo[1,2-a]pyridine-2-carboxylic acid ethylester. 6-Methyl-imidazo[1,2-a]pyridine-2-carboxylic acid and6-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester wereprepared in a similar manner to6-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid and its ester above.

Method P Preparation of4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazine-6-carboxylicacid Step1:4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazine-6-carboxylicacid methyl ester

To a solution of4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidmethyl ester (1 g) in dichloromethane (25 ml) was added 32% peraceticacid dropwise over 10 minutes. The reaction mixture was stirred at roomtemperature for 48 hours and then diluted with dichloromethane. Theorganic phase was washed once with water, twice with aqueous sodiumsulfite solution, and once with saturated aqueous sodium bicarbonate.The organic phase was dried over magnesium sulfate, filtered, and thesolvent evaporated to give the sub-title compound as a solid (1.012 g).

¹H NMR (399.978 MHz, CDCl₃) δ 3.58 (3H, s), 4.00 (3H, s), 4.27 (2H, s),7.96-7.99 (2H, m), 8.04-8.06 (1H, m).

Step 2: 4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1 ¹⁶-benzo[1,4]thiazine-6-carboxylic acid

To a solution of 4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-116-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1 g, from step 1)in MeOH (7 ml) was added dropwise a solution of sodium hydroxide (0.6 g)in water (5 ml). The reaction mixture was stirred at room temperaturefor 1 hour, diluted with water, cooled in an ice/water bath. Slowacidification with HCl (1N) to pH 2 yielded a precipitate which wasisolated by filtration to give the title compound (0.595 g) as a solid.

¹H NMR (399.978 MHz, DMSO-D6) δ 3.49 (3H,s), 4.91 (2H,s), 7.90-8.03(3H,m).

Method Q Preparation of4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl Step a:4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl-1′-carboxylic acidtert-butyl ester

To a solution of 4-(4-methanesulfonyl-phenoxy)-piperidine (0.7 g)dissolved in THF (5 ml) and 1,2-dichloroethane (10 ml) with1-Boc-4-piperidone (0.71 g) was added NaBH(OAc)₃ (0.926 g) and aceticacid (0.18 g). After 16 hours at RT aqueous NaOH (1M) solution anddichloromethane were added and the mixture was extracted withdichloromethane. The combined organic extracts were washed with water,dried with magnesium sulfate and concentrated to leave a residue whichwas purified by chromatography (dichloromethane:methanol 90:10) to givethe sub-title product (1.1 g; MS: APCI⁺(M+H) 439).

Step b: 4-(4-methanesulfonyl-phenoxy)-[1,4′]bipiperidinyl

The product of step a was dissolved in dichloromethane (20 ml) andtrifluoroacetic acid (5 ml) was added. After 16 hours at roomtemperature the solution was evaporated to leave the title compound as aTFA salt. The free base (0.7 g; oil; MS: APCI⁺(M+H) 339) was liberatedby addition of aqueous NaOH (1M) and extraction with dichloromethanefollowed by evaporation of the solvent.

3-Methanesulfonyl-5-nitro-benzoic acid and3-cyano-5-methanesulfonyl-benzoic acid can be prepared according to amethod described in EP-A1-556674.

2-amino-5-MeSO₂-benzoic acid can be prepared according to a methoddescribed in J. Org. Chem. (1953) 18 1380.

3-Ethanesulfonyl-benzoic acid can be prepared according to a methoddescribed in J. Chem. Soc. 1946, 763.

3-Methylsulfamoyl-benzoic acid and 3-dimethylsulfamoyl-benzoic acid canbe prepared according to a method described in DE2133038.3-Methylsulfamoyl-benzoic acid ¹H NMR: (399.98 MHz, DMSO-D6) δ 7.42 (3H,d), 7.63 (1H, q), 7.76 (1H, t), 8.01 (1H, m), 8.18 (1H, dt), 8.31 (1H,t), 13.48 (1H, s).

Other intermediates can be prepared by literature methods, by adaptationof literature methods or are available commercially. For example:

-   -   (2-methyl-4-nitro-2H-pyrazol-3-yl)methanecarboxylic acid,        2-{1-[sulfonyl chloride]-ethyl}-isoindole 1,3-dione and        (1,3-dimethyl-3,7-dihydro-purine-2,6-dion-8-yl)methanecarboxylic        acid are available from Salor (Aldrich Chemical Company Inc 1001        West Saint Paul Avenue Milwaukee, Wis. 53233 USA);    -   [4-amino-5-(iso-propyl-sulfonyl)-thiophen-3-yl]carboxylic acid,        [3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-isoxazol-4-yl]carboxylic        acid, 3-cyano-4-(pyrrol-1-yl)-thiophen-5-yl)carboxylic acid,        4-isopropylsulfanyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic        acid and        1-cyclopropyl-5-methoxy-2-methyl-2,3-dihydro-1H-indole-3-carboxylic        acid, (5-(isoxazol-3-yl)-thiophen-2-yl)sulfonyl chloride,        4-bromo-1-methyl-1H-pyrazol-3-ylmethanal,        4-chloro-1H-pyrazol-3-ylmethanal and        1-(4-chloro-benzyl)-1H-pyrazol-3-ylmethanal are available from        Maybridge Chemical Company Ltd.; Trevillett, Tintagel, Cornwall        PL34 0HW, UK;    -   (5-methanesulfonyl-1H-indol-2-yl)carboxylic acid is available by        hydrolysis of an ester available from Maybridge Chemical Company        Ltd., details above;    -   (4-chloro-5-methyl-3-nitro-pyrazol-1-yl)methanecarboxylic acid,        (5-methyl-3,4-dinitro-pyrazol-1-yl)methanecarboxylic acid and        (2,4-dinitro-imidazol-1-yl)methanecarboxylic acid are available        from ASINEX Ltd., 6 Schukinskaya ulitsa, Moscow 123182, Russia;    -   (6-(imidazol-1-yl)-pyridin-3-yl)carboxylic acid and        2-methyl-2-([1,2,4]triazol-1-yl) -propanoic acid are available        from Bionet Research Ltd, 3 Highfield Industrial Estate,        Camelford, Cornwall PL32 9QZ, UK; and,    -   (2-methyl-[1,8]naphthyridin-3-yl)carboxylic acid,        (2-methyl-[1,6]naphthyridin-3-yl)carboxylic acid and        (5-trifluoromethyl-thieno[3,2-b]pyridin-6-yl)-methanecarboxylic        acid are available from Peakdale Fine Chemicals Ltd., 7        Brookfield Industrial Estate, Glossop, Derbyshire, SK13 6LQ, UK.

EXAMPLE 28 Pharmacological Analysis: Calcium Flux [Ca²⁺]_(i) Assay

Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassiumsolution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 m M, Na₂CO₃ 8.5mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4) for one hourat room temperature. After loading, cells were centrifuged at 200 g for5 min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cells were thentransferred to 96 well FLIPr plates (Poly-D-Lysine plates from BectonDickinson pre-incubated with 5 μM fibronectin for two hours) at 25μl/well. The plate was centrifuged at 200 g for 5 min and the cells werewashed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1% (v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (I_(Ex)=490 nm and I_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMIcontaining 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate andsupplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μlof either vehicle or compound (100×required final concentration in 10%DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loadedby adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containinga concentration of a compound according to the Examples or solvent tothe lower wells of the chemotaxis plate. The filter was then placed overthe wells and 25 μl of eosinophil suspension were added to the top ofthe filter. The plate was incubated for 1 hr at 37° C. in a humidifiedincubator with a 95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS containing 0.5% Triton×100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

Compounds of the Examples were found to be antagonists of the eotaxinmediated human eosinophil chemotaxis.

EXAMPLE 29

Guinea-Pig Isolated Trachea

(See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984)European J. Pharmacol., 106, 405-409.)

Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervicaldislocation and the whole trachea removed. After clearing the adherentconnective tissue, the trachea was cut into six ring segments each threecartilage bands wide and then suspended in 20 ml organ baths containingKrebs-Henseleit solution of the following composition (mM): NaCl 117.6,NaH₂PO₄ 0.9, NaHCO₃ 25.0, MgSO₄ 1.2, KCl 5.4, CaCl₂ 2.6 and glucose11.1. The buffer was maintained at 37° C. and gassed with 5% CO₂ inoxygen. Indomethacin (2.8 μM) was added to the Krebs solution to preventdevelopment of smooth muscle tone due to the synthesis ofcyclo-oxygenase products. The tracheal rings were suspended between twoparallel tungsten wire hooks, one attached to an Ormed beam isometricforce transducer and the other to a stationary support in the organbath. Changes in isometric force were recorded on 2-channel Sekonic flatbed chart recorders.

Experimental Protocols

At the beginning of each experiment a force of 1 g was applied to thetissues and this was reinstated over a 60 minute equilibration perioduntil a steady resting tone was achieved. Subsequently, a cumulativehistamine concentration effect (E/[A]) curve was constructed at 0.5log₁₀ unit increments, in each tissue. The tissues were then washed andapproximately 30 minutes later, test compound or vehicle (20% DMSO) wasadded. Following an incubation period of 60 minutes a second E/[A] curvewas performed to histamine.

Contraction responses were recorded as a percentage of the first curvemaximum.

Data Analysis

Experimental E/[A] curve data were analysed for the purposes ofestimating the potencies (p[A₅₀] values) of histamine in the absence andpresence of the test compound. Affinity (pA₂) values of test compoundswere subsequently calculated using the following equation:log(r−1)=log[B]+pA ₂where r=[A]₅₀ in presence of test compound/[A]₅₀ in absence ofantagonist and [B] is the concentration of test compound. Compounds ofthe Examples were found to be H1 antagonists.

1. A compound of the following formula:

wherein: X is CH₂, R¹ is phenyl substituted with one or more offluorine, chlorine, or C₁₋₄ alkyl; R³ is phenyl optionally substitutedby halo; hydroxyl; nitro; cyano; amino; C₁₋₄ alkyl which optionallysubstituted by S(O)₂(C₁₋₄alkyl) or S(O)₂ phenyl; C₁₋₄ alkoxy;S(O)_(k)R⁴⁶ in which k is 0, 1, or 2 and R⁴⁶ is C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) or phenyl; C₁₋₄ haloalkylthio,C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) orS(O)₂N(C₁₋₄ alkyl); or a pharmaceutically acceptable salt thereof; or asolvate thereof.
 2. The compound of claim 1 in which halogen substitutedphenyl is phenyl substituted with one or two chlorine atoms or with oneor two fluorine atoms.
 3. The compound of claim 1 in which R1 is3,4-dichorophenyl.
 4. The compound of claim 1 in which R3 isCH₃S(O)₂-phenyl-.
 5. A compound of the following formula:

wherein: R₁ is 3,4-dichorophenyl, X is —CH₂—, and R₃ is CH₃S(O)₂-phenyl,or a pharmaceutically acceptable salt thereof; or a solvate thereof.